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99 records returned

Ankyrin regulates K(ATP) channel membrane trafficking and gating in excitable cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
K(ATP) channels play critical roles in many cellular functions by coupling cell metabolic status to electrical activity. First discovered in cardiomyocytes,(1) K(ATP) channels (comprised of Kir6.x and SUR subunits) have since been found in many other tissues, including pancreatic beta cells, skeletal muscle, smooth muscle, brain, pituitary and kidney. By linking cellular metabolic state with membrane potential, K(ATP) channels are able to regulate a number of cellular functions such as hormone secretion, vascular tone and excitability. Specifically, a reduction in metabolism causes a decrease in the ATP:ADP ratio, open...
Source: Channels - November 12, 2009 Category: Molecular Biology Authors: Kline CF, Hund TJ, Mohler PJ Tags: Channels (Austin) Source Type: journals

A novel N-terminal motif of dipeptidyl peptidase-like proteins produces rapid inactivation of K(V)4.2 channels by a pore-blocking mechanism.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The somatodendritic subthreshold A-type K(+) current in neurons (I(SA)) depends on its kinetic and voltage-dependent properties to regulate membrane excitability, action potential repetitive firing, and signal integration. Key functional properties of the K(V)4 channel complex underlying I(SA) are determined by dipeptidyl peptidase-like proteins known as dipeptidyl peptidase 6 (DPP6) and dipeptidyl peptidase 10 (DPP10). Among the multiple known DPP10 isoforms with alternative N-terminal sequences, DPP10a confers exceptionally fast inactivation to K(V)4.2 channels. To elucidate the molecular basis of this fast inactivat...
Source: Channels - November 12, 2009 Category: Molecular Biology Authors: Jerng HH, Dougherty K, Covarrubias M, Pfaffinger PJ Tags: Channels (Austin) Source Type: journals

Kelch-like 1 protein upregulates T-type currents by an actin-F dependent increase in alpha(1H) channels via the recycling endosome.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this report we further elucidate the role of the actin cytoskeleton in this process using pharmacological tools to disrupt or stabilize actin filaments and to prevent protein trafficking and vesicle recycling. Disruption of the cytoskeleton did not affect the basal activity of alpha(1H), but did eliminate its modulation by KLHL1. In contrast, actin-F stabilization on its own increased basal alpha(1H) activity similar to KLHL1 but without synergy in its presence, suggesting KLHL1 requires actin-polymerization to increase alpha(1H) currents. Noise analysis revealed that actin polymerization induced an increase in N and P(...
Source: Channels - October 8, 2009 Category: Molecular Biology Authors: Aromolaran KA, Benzow KA, Cribbs LL, Koob MD, Piedras-Rentería ES Tags: Channels (Austin) Source Type: journals

Stabilization of Ca current in Purkinje neurons during high-frequency firing by a balance of Ca-dependent facilitation and inactivation.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Purkinje neurons fire spontaneous action potentials at approximately 50 spikes/sec and generate more than 100 spikes/sec during cerebellum-mediated behaviors. Many voltage-gated channels, including Ca channels, can inactivate and/or facilitate with repeated stimulation, raising the question of how these channels respond to regular, rapid trains of depolarizations. To test whether Ca currents are modulated during firing, we recorded voltage-clamped Ca currents, predominantly carried by P-type Ca channels, from acutely dissociated mouse Purkinje neurons at 30-33 degrees C (1 mM Ca). With 0.5 mM intracellular EGTA, 1-seco...
Source: Channels - October 8, 2009 Category: Molecular Biology Authors: Benton MD, Raman IM Tags: Channels (Austin) Source Type: journals

K(V)4.3 expression and gating: S2 and S3 acidic and S4 innermost basic residues.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Effects of neutralizing individual negatively charged (acidic [E,D]) and innermost positively charged (basic [K,R]) residues in transmembrane segments S2 (D230Q, E240Q), S3 (D263Q) and S4 (K299A/Q, R302A/Q) of the K(V)4.3 putative voltage sensing domain (VSD) were determined. S2 D230Q generated large macroscopic currents, depolarized steady-state activation ("a(4)") and isochronal (1 sec) inactivation ("i") relationships, and significantly accelerated kinetics of deactivation and recovery (from both macroscopic and closed state inactivation [CSI]). D230Q thus stabilized non-inactivated closed states. These effects were...
Source: Channels - October 8, 2009 Category: Molecular Biology Authors: Skerritt MR, Campbell DL Tags: Channels (Austin) Source Type: journals

Visualizing the mapped ion pathway through the Na,K-ATPase pump.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The Na(+),K(+)-ATPase pump achieves thermodynamically uphill exchange of cytoplasmic Na(+) ions for extracellular K(+) ions by using ATP-mediated phosphorylation, followed by autodephosphorylation, to power conformational changes that allow ion access to the pump's binding sites from only one side of the membrane at a time. Formally, the pump behaves like an ion channel with two tightly coupled gates that are constrained to open and close alternately. The marine agent palytoxin disrupts this coupling, allowing both gates to sometimes be open, so temporarily transforming a pump into an ion channel. We made a cysteine sc...
Source: Channels - October 8, 2009 Category: Molecular Biology Authors: Takeuchi A, Reyes N, Artigas P, Gadsby DC Tags: Channels (Austin) Source Type: journals

Complementary conductance changes by I(Kx) and I(h) contribute to membrane impedance stability during the rod light response.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In addition to the HCN1 channels that mediate the h current, the Kx current also performs signal filtering in rod photoreceptors. This current is known to be mediated by potassium channels and has similarities to the neuronal M current and EAG potassium channels. Although it is known that in filtering the light response of rods, I(h) and I(Kx) undergo complementary conductance changes, the qualities and significance of these changes are not clear. Here we present an analysis demonstrating the filtering effect of HCN1 channels in salamander rods when I(Kx) is blocked, and a simulation of the rod light response showing t...
Source: Channels - August 30, 2009 Category: Molecular Biology Authors: Barrow AJ, Wu SM Tags: Channels (Austin) Source Type: journals

Characterization of the calmodulin-binding site in the N terminus of Ca(V)1.2.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Interaction of calmodulin (CaM) with the C-terminus (CT) of the L-type Ca(V)1.2 channel is crucial for Ca(2+)-dependent inactivation (CDI). CaM also binds to the N-terminus (NT), and a CaM-formed "bridge" between CT and NT has been proposed to control CDI. We characterized the interaction of CaM with its NT-binding peptide. Binding is Ca(2+)-dependent with an affinity of 0.6 muM. Mutations in NT of Ca(V)1.2 that abolished the binding of CaM only slightly weakened the CDI but also accelerated the VDI. CaM did not foster an interaction between the CaM-binding peptides of NT and CT. Thus, the role of CaM's interaction wit...
Source: Channels - August 30, 2009 Category: Molecular Biology Authors: Benmocha A, Almagor L, Oz S, Hirsch JA, Dascal N Tags: Channels (Austin) Source Type: journals

Carbenoxolone inhibits volume-regulated anion conductance in cultured rat cortical astroglia.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Accumulating evidence indicate that the gap-junction inhibitor carbenoxolone (CBX) regulates neuronal synchronization, depresses epileptiform activity and has a neuroprotective action. These CBX effects do not depend solely on its ability to inhibit gap junction channels formed by connexins (Cx), but the underlying mechanisms remain to be elucidated. Here we addressed the questions whether CBX modulates volume-regulated anion channels (VRAC) involved in the regulatory volume decrease and regulates the associated release of excitatory amino acids in cultured rat cortical astrocytes. We found that CBX inhibits VRAC condu...
Source: Channels - August 30, 2009 Category: Molecular Biology Authors: Benfenati V, Caprini M, Nicchia GP, Rossi A, Dovizio M, Cervetto C, Nobile M, Ferroni S Tags: Channels (Austin) Source Type: journals

The helical character of the S6 segment of TRPV1 channels.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The era of molecular structure of ion channels has revealed that their transmembrane segments are alpha helices, as was suspected from hydropathy analysis and experimental data. TRP channels are recent additions to the known families of ion channels, and little structural data is available. In a recent work, we explored the conformational changes occurring at the putative S6 segment of TRPV1 channels; and we observed a periodicity of chemical modification of residues suggestive of an alpha helical structure. Further analysis of the periodicity of the disposition of hydrophobic residues in the S6 segment, suggests that ...
Source: Channels - August 30, 2009 Category: Molecular Biology Authors: Islas LD, Salazar H, Jara-Oseguera A, Nieto-Posadas A, Llorente I, Rangel-Yescas G, Rosenbaum T Tags: Channels (Austin) Source Type: journals

Voltage-dependent conformational changes of K(V)AP S4 segment in bacterial membrane environment.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The nature and magnitude of voltage sensor conformational changes during ion channel activation are controversial. We have analyzed the topology of the K(V)AP voltage sensor domain in the absence and presence of a hyperpolarized voltage using native, right-side out membrane vesicles from E. coli. This approach does not disrupt the normal membrane environment of the channel protein and does not involve detergent solubilization. We found that voltage-dependent conformational changes are focused in the N-terminal half of the K(V)AP S4 segment, in excellent agreement with results obtained with Shaker. Homologous residues i...
Source: Channels - August 30, 2009 Category: Molecular Biology Authors: Koag MC, Papazian DM Tags: Channels (Austin) Source Type: journals

The molecular basis for the actions of K(V)beta1.2 on the opening and closing of the K(V)1.2 delayed rectifier channel.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Cytosolic K(V)beta1 subunits co-assemble with transmembrane K(V)1 channel alpha-subunits and have complex effects on channel function. Fast inactivation, the most obvious effect conferred, is due to fast open channel block resulting from the binding of the N-terminus within the inner mouth of the pore. K(V)beta1 subunits also slow current deactivation, enhance slow inactivation and shift channel activation to more negative voltages, but the mechanisms underlying these actions are not known. Here we use voltage clamp fluorimetry at sites near the extracellular end of the S4 helix, the channel's primary voltage sensor, i...
Source: Channels - August 30, 2009 Category: Molecular Biology Authors: Peters CJ, Vaid M, Horne AJ, Fedida D, Accili EA Tags: Channels (Austin) Source Type: journals

Transcriptional and electrophysiological consequences of KChIP2-mediated regulation of Ca(V)1.2.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Potassium channel interacting proteins (KChIP) are Ca(2+)-binding proteins that originally were identified as auxiliary subunits for K(V)4 channels. K(V)4 channels encode the voltage gated A-current (I(A)) in neuronal tissue and the fast, transient outward current (I(to,f)) in cardiac tissue. Recently, we have reported that KChIP2 functionally modulates the cardiac Ca(V)1.2-governed L-type Ca(2+) current (I(Ca,L)) through a direct interaction between KChIP2 and the amino-terminus of Ca(V)1.2. Here, we show that KChIP2 and Ca(V)1.2 co-immunoprecipitate enhancing the biochemical support for our previous finding. Using ge...
Source: Channels - August 30, 2009 Category: Molecular Biology Authors: Thomsen MB, Foster E, Nguyen KH, Sosunov EA Tags: Channels (Austin) Source Type: journals

Alternative splicing of TRIP8b diversifies its actions as an accessory subunit of neuronal HCN channels.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19690453 [PubMed - as supplied by publisher] (Source: Channels)
Source: Channels - July 26, 2009 Category: Molecular Biology Authors: Braun AP Tags: Channels (Austin) Source Type: journals

Synaptic NMDAR activity suppresses FOXO1 expression via a cis-acting FOXO binding site: FOXO1 is a FOXO target gene.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Activation of gene expression by FOXO transcription factors can promote neuronal death in response to loss of trophic support, or oxidative stress. The predominant neuronal FOXOs, FOXO1 and FOXO3, promote the expression of pro-death genes, such as Fas Ligand, Bim and Txnip. Neuroprotective signals initiated by neurotrophins, growth factors or synaptic activity trigger the nuclear export of FOXOs via activation of the PI3K-Akt pathway. One key aspect of FOXO regulation is that once PI3K-Akt activity has returned to baseline, FOXOs return to the nucleus to resume the activation of their target genes. Thus, the FOXO-inhib...
Source: Channels - July 23, 2009 Category: Molecular Biology Authors: Al-Mubarak B, Soriano FX, Hardingham GE Tags: Channels (Austin) Source Type: journals

The cardiac alpha(1C) subunit can support excitation-triggered Ca(2+) entry in dysgenic and dyspedic myotubes.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Depolarization-induced entry of divalent ions into skeletal muscle has been attributed to a process termed Excitation-Coupled Ca(2+) Entry (ECCE), which is hypothesized to require the interaction of the ryanodine receptor (RyR1), the L-type Ca(2+) channel (DHPR) and another unidentified cation channel. Thus, ECCE is absent in myotubes lacking either the DHPR (dysgenic) or RyR1 (dyspedic). Furthermore, ECCE, as measured by Mn(2+) quench of Fura-2, is reconstituted by expression of a mutant DHPR alpha(1S) subunit (SkEIIIK) thought to be impermeable to divalent cations. Previously, we showed that the bulk of depolarizatio...
Source: Channels - July 23, 2009 Category: Molecular Biology Authors: Bannister RA, Beam KG Tags: Channels (Austin) Source Type: journals

Comparative effects of H(+) and Ca(2+) on large-conductance Ca(2+)- and voltage-gated Slo1 K(+) channels.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we examined the comparative mechanisms of the channel activation by Ca(2+) and H(+). Steady-state macroscopic conductance-voltage measurements as well as single-channel openings at negative voltages where voltage-sensor activation is negligible showed that at respective saturating concentrations Ca(2+) is more effective in relative stabilization of the open conformation than H(+). Calculations using the Debye-Hückel formalism suggest that small structural changes in the RCK1 sensor, on the order of few angstroms, may accompany the H(+)-mediated opening of the channel. While the efficacy of H(+) in activ...
Source: Channels - July 16, 2009 Category: Molecular Biology Authors: Hou S, Horrigan FT, Xu R, Heinemann SH, Hoshi T Tags: Channels (Austin) Source Type: journals

Extracellular potassium dependency of block of HERG by quinidine and cisapride is primarily determined by the permeant ion and not by inactivation.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, HERG block by quinidine and cisapride was assessed in extracellular solutions of calcium, potassium, rubidium, cesium and tetraethylammonium (TEA) using two-electrode voltage clamping of Xenopus oocytes. Consistent with previous reports we show that increases in extracellular potassium reduce HERG block by quinidine and cisapride. We also show that increasing extracellular rubidium and cesium reduced HERG block by quinidine and cisapride whereas increasing extracellular calcium and extracellular TEA did not alter HERG block by quinidine and cisapride. These results demonstrate that at lower extracellular pot...
Source: Channels - July 14, 2009 Category: Molecular Biology Authors: Barrows B, Cheung K, Bialobrzeski T, Foster J, Schulze J, Miller A Tags: Channels (Austin) Source Type: journals

Regulation of N-type calcium channels by G-proteins: Multiple pathways to control calcium entry into neurons.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19617715 [PubMed - as supplied by publisher] (Source: Channels)
Source: Channels - July 14, 2009 Category: Molecular Biology Authors: Weiss N Tags: Channels (Austin) Source Type: journals

TRPC channels as STIM1-regulated SOCs.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Store-operated Ca(2+) channels (SOCs) are Ca(2+) influx channels at the plasma membrane whose opening is determined by the level of Ca(2+) stored in the endoplasmic reticulum lumen. SOCs are activated in response to receptor-mediated or passive depletion of ER Ca(2+) to regulate many Ca(2+)-dependent cellular functions. Early work implicated the TRPC channels as SOCs. More recently, it was found that the Orai channels mediate the CRAC current and that the Ca(2+) binding protein STIM1 functions as the ER Ca(2+) sensor that mediates activation of the SOCs in response to depletion of ER Ca(2+). Key questions are whether b...
Source: Channels - July 6, 2009 Category: Molecular Biology Authors: Yuan JP, Kim MS, Zeng W, Shin DM, Huang G, Worley PF, Muallem S Tags: Channels (Austin) Source Type: journals

Reliability of triggering postinhibitory rebound bursts in deep cerebellar neurons.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Deep cerebellar nuclear (DCN) neurons exhibit distinct phenotypes of rebound discharge following current-evoked membrane hyperpolarizations that arise from specific Ca(V)3 T-type Ca(2+) channel isoforms and Ca(2+)-activated K(+) channels. The probability of evoking rebound bursts following a brief train of GABAergic inhibitory synaptic input from cerebellar Purkinje cells was recently questioned for stimulus intensities adjusted to evoke a long post-stimulus pause in spike firing. We revisited this issue to examine the potential for generating rebound bursts in DCN cells in response to synaptic inputs in vitro. Both a ...
Source: Channels - May 28, 2009 Category: Molecular Biology Authors: Tadayonnejad R, Mehaffey WH, Anderson D, Turner RW Tags: Channels (Austin) Source Type: journals

UNC80 functions as a scaffold for Src kinases in NALCN channel function.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Ion channels can be regulated by a wide spectrum of neurotransmitters and hormones, largely through G-protein-coupled receptors (GPCRs). G-protein-independent activation of ion channel currents by GPCRs has also been recorded, although the molecular identity of the channels and the activation mechanisms remain largely unknown. UNC80 is a protein that is associated with the NALCN Na(+) leak cation channel, and is required for the activation of this channel by the neuropeptide substance P through GPCRs in a G-protein-independent fashion. Here, we show that UNC80 binds Src kinases and recruits Src into the channel complex...
Source: Channels - May 26, 2009 Category: Molecular Biology Authors: Wang H, Ren D Tags: Channels (Austin) Source Type: journals

Linoleic acid inhibits TRP channels with intrinsic voltage sensitivity: Implications on the mechanism of linoleic acid action.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Open channel block (OCB) is a process by which ions bind to the inside of a channel pore and block the flow of ions through that channel. Repulsion of the blocking ions by membrane depolarization is a known mechanism for open channel block removal. For the N-methyl-D-aspartate (NMDA) channel, this mechanism is necessary for channel activation and is involved in neuronal plasticity. Several types of Transient Receptor Potential (TRP) channels, including the Drosophila TRP and TRP-Like (TRPL) channels, also exhibit open channel block. For the Drosophila TRP and TRPL channels, removal of open channel block is necessary fo...
Source: Channels - May 25, 2009 Category: Molecular Biology Authors: Parnas M, Peters M, Minke B Tags: Channels (Austin) Source Type: journals

Functional TRPV4 channels and an absence of capsaicin-evoked currents in freshly-isolated, guinea-pig urothelial cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Previously we have shown that the transient receptor potential vanilloid 4 (TRPV4) channel regulates urinary bladder function, and that TRPV4 is expressed in both smooth muscle and urothelial cell types within the bladder wall.(1) Urothelial cells have also been suggested to express TRPV1 channels.(2) Therefore, we enzymatically isolated guinea-pig urothelial cells in an attempt to record TRPV4 and TRPV1-mediated currents. The identity of the isolated cells was confirmed by quantitative PCR for the urothelial marker uroplakin 1A. Whole-cell patch-clamp recordings with the TRPV4 agonist, GSK1016790A, activated urothelia...
Source: Channels - May 23, 2009 Category: Molecular Biology Authors: Xu X, Gordon E, Lin Z, Lozinskaya IM, Chen Y, Thorneloe KS Tags: Channels (Austin) Source Type: journals

Role of the terminal domains in sodium channel localization.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, chimeras generated between Na(V)1.2 and Na(V)1.6 were used to test channel domains for sequence that would allow Na(V)1.2 to localize to unmyelinated axons when Na(V)1.6 could not. We show that the N-terminal 202 amino acids of the Na(V)1.2 channel can mediate membrane domain-specific sorting in polarized epithelial cells and are necessary but not sufficient for localizing the isoform to the axons of cultured neurons. The domain-sorting signal is in the region between amino acids 110-202 of the Na(V)1.2 channel. The C-terminal 451 amino acids of Na(V)1.2 likely contain determinants that interact with neuron-...
Source: Channels - May 23, 2009 Category: Molecular Biology Authors: Lee A, Goldin AL Tags: Channels (Austin) Source Type: journals

Reassessing the molecular mechanism of beta-adrenergic stimulation of cardiac L-type Ca(2+) current.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19535897 [PubMed - as supplied by publisher] (Source: Channels)
Source: Channels - May 20, 2009 Category: Molecular Biology Authors: Bannister RA, Ohrtman JD Tags: Channels (Austin) Source Type: journals

Distinct post-translational modifications regulate BK channel activity: The interplay between protein palmitoylation and phosphorylation.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19556862 [PubMed - as supplied by publisher] (Source: Channels)
Source: Channels - May 11, 2009 Category: Molecular Biology Authors: Braun AP Tags: Channels (Austin) Source Type: journals

Electrical activity and exocytotic correlates of biphasic insulin secretion from beta-cells of canine islets of Langerhans: Contribution of tuning two modes of Ca(2+) entry-dependent exocytosis to two modes of glucose-induced electrical activity.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Biphasic insulin secretion in response to glucose, consisting of a transient first phase followed by a progressive second phase, is well described in pancreatic islets. Using single canine beta-cells we have compared the time courses of electrical activity and insulin granule exocytosis to biphasic insulin secretion. Short trains of action potentials, similar those found during first phase insulin secretion, trigger phasic exocytosis from a small pool of insulin granules, likely an immediately releasable pool docked near voltage activated Ca(2+) channels. In contrast, plateau depolarizations to between -35 and -20 mV r...
Source: Channels - May 10, 2009 Category: Molecular Biology Authors: Misler S, Zhou Z, Dickey AS, Silva AM, Pressel DM, Barnett DW Tags: Channels (Austin) Source Type: journals

Re-evaluating membrane transport processes: New insights and appreciation of protein behavior.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19556861 [PubMed - as supplied by publisher] (Source: Channels)
Source: Channels - May 10, 2009 Category: Molecular Biology Authors: Braun AP Tags: Channels (Austin) Source Type: journals

Ca(V)2.1 P/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations: Implications for calcium channelopathies.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Alternative splicing is known to generate multiple functionally distinct calcium channel variants that exhibit unique spatial and temporal expression patterns. In humans, naturally occurring mutations in genes encoding calcium channel pore forming alpha(1)-subunits are associated with several severe hereditary disorders although it remains to be described whether there exists any relationship between the physiological effects of these mutations and calcium channel splice variation. In the present study, we systematically compare the biophysical effects of three type-1 familial hemiplegic migraine (FHM-1) mutations in t...
Source: Channels - March 1, 2009 Category: Molecular Biology Authors: Adams PJ, Garcia E, David LS, Mulatz KJ, Spacey SD, Snutch TP Tags: Channels (Austin) Source Type: journals

Phasic and tonic modes of depolarization-exocytosis coupling in beta-cells of porcine islets of Langerhans.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In response to depolarizations that open voltage dependent Ca(2+) channels single porcine beta-cells display heterogeneous time courses of exocytosis. Some cells display phasic exocytosis that is triggered by individual or short burst of action potentials typically characteristic of glucose-induced electrical activity or brief voltage clamp depolarization. Other cells, singularly or additionally, display tonic exocytosis that (i) is triggered during prolonged (up to seconds-long) depolarizations to voltages (-30 to -20 mV), and (ii) coincides with rises in global cytosolic [Ca(2+)] >500 nM. We suggest that tonic exo...
Source: Channels - March 1, 2009 Category: Molecular Biology Authors: Misler S, Silva AM, Barnett D, Dickey AS Tags: Channels (Austin) Source Type: journals

Ion channels underlying stimulus-exocytosis coupling and its cell-to-cell heterogeneity in beta-cells of transplantable porcine islets of Langerhans.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Given the growing interest in porcine islets as model tissue for studying the pathogenesis of human diabetes mellitus and its treatment by transplantation, we investigated stimulus-exocytosis coupling in single porcine beta-cells using patch clamp electrophysiology, Ca(2+) imaging, capacitance tracking and amperometry. We establish that porcine beta-cells display several features prominently seen in beta-cells from human islets of Langerhans. These include: (i) wide heterogeneity of electrical responsiveness to glucose; (ii) dependence of action potential activity on voltage-dependent Na(+) as well as high voltage acti...
Source: Channels - March 1, 2009 Category: Molecular Biology Authors: Silva AM, Dickey AS, Barnett DW, Misler S Tags: Channels (Austin) Source Type: journals

Synergistic and antagonistic interactions between tetrodotoxin and mu-conotoxin in blocking voltage-gated sodium channels.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Tetrodotoxin (TTX) is the quintessential ligand of voltage-gated sodium channels (Na(V)s). Like TTX, mu-conotoxin peptides are pore blockers, and both toxins have helped to define the properties of neurotoxin receptor Site 1 of Na(V)s. Here, we report unexpected results showing that the recently discovered mu-conotoxin KIIIA and TTX can simultaneously bind to Site 1 and act in concert. Results with saturating concentrations of peptide applied to voltage-clamped Xenopus oocytes expressing brain Na(V)1.2, and single-channel recordings from brain channels in lipid bilayers, show that KIIIA or its analog, KIIIA[K7A], block...
Source: Channels - January 25, 2009 Category: Molecular Biology Authors: Zhang MM, McArthur JR, Azam L, Bulaj G, Olivera BM, French RJ, Yoshikami D Tags: Channels (Austin) Source Type: journals

Functional properties of the Ca(V)1.2 calcium channel activated by calmodulin in the absence of alpha(2)delta subunits.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Voltage-activated Ca(V)1.2 calcium channels require association of the pore-forming alpha(1C) subunit with accessory Ca(V)beta and alpha(2)delta subunits. Binding of a single calmodulin (CaM) to alpha(1C) supports Ca(2+)-dependent inactivation (CDI). The human Ca(V)1.2 channel is silent in the absence of Ca(V)beta and/or alpha(2)delta. Recently, we found that coexpression of exogenous CaM (CaM(ex)) supports plasma membrane targeting, gating facilitation and CDI of the channel in the absence of Ca(V)beta. Here we discovered that CaM(ex) and its Ca(2+)-insensitive mutant (CaM(1234)) rendered active alpha(1C)/Ca(V)beta ch...
Source: Channels - December 26, 2008 Category: Molecular Biology Authors: Ravindran A, Kobrinsky E, Lao QZ, Soldatov NM Tags: Channels (Austin) Source Type: journals

KCNE variants reveal a critical role of the beta subunit carboxyl terminus in PKA-dependent regulation of the I(Ks) potassium channel.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Co-assembly of KCNQ1 with different accessory, or beta, subunits that are members of the KCNE family results in potassium (K(+)) channels that conduct functionally distinct currents. The alpha subunit KCNQ1 conducts a slowly activated delayed rectifier K(+) current (I(Ks)), a major contributor to cardiac repolarization, when co-assembled with KCNE1 and channels that favor the open state when co-assembled with either KCNE2 or KCNE3. In the heart, stimulation of the sympathetic nervous system enhances I(Ks). A macromolecular signaling complex of the I(Ks) channel including the targeting protein Yotiao coordinates up or d...
Source: Channels - December 17, 2008 Category: Molecular Biology Authors: Kurokawa J, Bankston JR, Kaihara A, Chen L, Furukawa T, Kass RS Tags: Channels (Austin) Source Type: journals

Rapid outer pore movements after opening in a K(V)1 potassium channel are revealed by TMRM fluorescence from the S3-S4 linker, and modulated by extracellular potassium.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Fluorescence-based approaches provide powerful techniques to directly report structural dynamics underlying gating processes in Shaker K(V) channels. Here, following on from work carried out in Shaker channels, we have used voltage clamp fluorimetry for the first time to study voltage sensor motions in mammalian K(V)1.5 channels, by attaching TMRM fluorescent probes to substituted cysteine residues in the S3-S4 linker of K(V)1.5 (A397C). Compared with the Shaker channel, there are significant differences in the fluorescence signals that occur on activation of the channel. In addition to a well-understood fluorescence q...
Source: Channels - December 17, 2008 Category: Molecular Biology Authors: Vaid M, Horne A, Claydon T, Fedida D Tags: Channels (Austin) Source Type: journals

Genetic selection of activatory mutations in KcsA.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study we have used a genetic complementation assay of K(+)-auxotrophic E. coli (TK2420) and S. cerevisiae (SGY1528) to identify activatory or 'gain-of-function' mutations which allow functional activity of KcsA in the physiological environment of two markedly different expression systems. These mutations clustered at the helix-bundle-crossing in both TM1 and TM2 (residues H25, L105, A108, T112, W113, F114, E118 and Q119), and include residues previously implicated in the pH-gating mechanism. We discuss how these gain-of-function mutations may result in their activatory phenotype, the relative merits of the E. coli ...
Source: Channels - September 18, 2008 Category: Molecular Biology Authors: Paynter JJ, Sarkies P, Andres-Enguix I, Tucker SJ Tags: Channels (Austin) Source Type: journals

Functional properties and modulation of extracellular epitope-tagged Ca(V)2.1 voltage-gated calcium channels.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Depolarisation-induced Ca(2+) influx into electrically excitable cells is determined by the density of voltage-gated Ca(2+) channels at the cell surface. Surface expression is modulated by physiological stimuli as well as by drugs and can be altered under pathological conditions. Extracellular epitope-tagging of channel subunits allows to quantify their surface expression and to distinguish surface channels from those in intracellular compartments. Here we report the first systematic characterisation of extracellularly epitope-tagged Ca(V)2.1 channels. We identified a permissive region in the pore-loop of repeat IV wit...
Source: Channels - September 18, 2008 Category: Molecular Biology Authors: Watschinger K, Horak SB, Schulze K, Obermair GJ, Wild C, Koschak A, Sinnegger-Brauns MJ, Tampé R, Striessnig J Tags: Channels (Austin) Source Type: journals

A role for cGMP-dependent protein kinase II in AMPA receptor trafficking and synaptic plasticity.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Regulated trafficking of AMPA receptors (AMPARs) is an important mechanism that underlies the activity-dependent modification of synaptic strength. Trafficking of AMPARs is regulated by specific interactions of their subunits with other proteins. Recently, we have reported that the AMPAR subunit GluR1 binds the cGMP-dependent kinase type II (cGKII) adjacent to the kinase catalytic site, and that this interaction is increased by cGMP. In this complex, cGKII phosphorylates GluR1 at serine 845 (S845), a site known to be phosphorylated also by PKA. S845 phosphorylation leads to an increase of GluR1 on the plasma membrane. ...
Source: Channels - August 4, 2008 Category: Molecular Biology Authors: Serulle Y, Arancio O, Ziff EB Tags: Channels (Austin) Source Type: journals

Molecular determinants of sensitivity and conductivity of human TRPM7 to Mg(2+) and Ca(2+).Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We examined the effects of neutralizing each of four negatively charged amino acid residues, Glu-1047, Glu-1052, Asp-1054 and Asp-1059, within the putative pore-forming region of human TRPM7. Mutating Glu-1047 to alanine (E1047A) resulted in non-functional channels, whereas mutating any of the other residues resulted in functionally expressed channels. Cs(+) currents through D1054A and E1052A were less sensitive to block by divalent cations; the IC(50) values were increased 5.5- and 3.9-fold, respectively, for Mg(2+) and 10.5- and 6.7-fold, respectively, for Ca(2+). D1059A also had a significant reduction, though less mark...
Source: Channels - July 30, 2008 Category: Molecular Biology Authors: Numata T, Okada Y Tags: Channels (Austin) Source Type: journals

Exploring the function and pharmacotherapeutic potential of voltage-gated Ca(2+) channels with gene Knockout models.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 18719397 [PubMed - as supplied by publisher] (Source: Channels)
Source: Channels - July 11, 2008 Category: Molecular Biology Authors: Striessnig J, Koschak A Tags: Channels (Austin) Source Type: journals

D2 dopamine receptors interact directly with N-type calcium channels and regulate channel surface expression levels.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
N-type channels are located on dendrites and at pre-synaptic nerve terminals where they play a fundamental role in neurotransmitter release. They are potently regulated by the activation of a number of different types of pertussis toxin (PTX)-sensitive Galpha(i/o) coupled receptors, which results in voltage-dependent inhibition of channel activity via Gbetagamma subunits. Using heterologous expression in HEK 293T cells, we show via whole cell patch clamp recordings that D2 receptors mediate both Gbetagamma (i.e., voltage-dependent) and voltage-independent inhibition of channel activity. Furthermore, using co-immunoprec...
Source: Channels - July 9, 2008 Category: Molecular Biology Authors: Kisilevsky AE, Zamponi GW Tags: Channels (Austin) Source Type: journals

A mutually exclusive alternative exon of slo1 codes for a neuronal BK channel with altered function.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels are comprised of four pore-forming alpha-subunits (Slo1), whose mRNA is alternatively spliced in a cell-specific manner. Here we report the first case of a correctly spliced mutually exclusive exon in a mammalian (human and mouse) BK channel; an exon coding for the region from S6 to the RCK1 domain is exchanged for an alternative exon of the same length. The slo1 transcript with this novel exon is present in native brain tissues and inclusion of the alternative exon profoundly alters the channel's gating characteristics: faster activation at low Ca(2+) ...
Source: Channels - July 8, 2008 Category: Molecular Biology Authors: Soom M, Gessner G, Heuer H, Hoshi T, Heinemann SH Tags: Channels (Austin) Source Type: journals

Slips, leaks and channels in glutamate transporters.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Glutamate transporters are unusual proteins in that they can function as both a transporter and a chloride channel. With the recent determination of the crystal structure of an archaeal aspartate transporter it is now possible to begin to put together a physical picture of how these proteins are able to carry out their dual functions. In this review we shall discuss our current understanding of the functional states of glutamate transporters and how they may arise. We will also discuss some of the alternate conducting states of glutamate transporters and provide definitions of the various states. PMID: 18690049 [Pu...
Source: Channels - January 1, 2008 Category: Molecular Biology Authors: Vandenberg RJ, Huang S, Ryan RM Tags: Channels (Austin) Source Type: journals

Ca2+ signaling in smooth muscle: TRPC6, NCX and LNats in nanodomains.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Following the recent observation of localized cytosolic subplasmalemmal [Na+] elevations (LNats) in rat aortic smooth muscle cells, we discuss here the current evidence for the structural and molecular roles of cytosolic nanodomains at close junctions of the plasma membrane (PM) and sarcoplasmic reticulum (SR) in the generation of LNats. These junctions, the loss of which might contribute to vascular aging and disease, provide a platform for ion metabolism signalplexes and the interaction of localized Na+ and Ca2+ gradients. We moreover suggest the existence in the junctions of a Na+ diffusional barrier as a necessary ...
Source: Channels - January 1, 2008 Category: Molecular Biology Authors: Poburko D, Fameli N, Kuo KH, van Breemen C Tags: Channels (Austin) Source Type: journals

Stoichiometry of Kir channels with phosphatidylinositol bisphosphate.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Phosphatidylinositol bisphosphate (PIP(2)) is the most abundant phosphoinositide in the plasma membrane of cells and its interaction with many ion channel proteins has proven to be a critical factor enabling ion channel gating. All members of the inwardly rectifying potassium (Kir) channel family depend on PIP(2) for their activity, displaying distinct affinities and stereospecificities of interaction with the phosphoinositide. Here, we explored the stoichiometry of Kir channels with PIP(2). We first showed that PIP(2) regulated the activity of Kir3.4 channels mainly by altering their bursting behavior. Detailed burst ...
Source: Channels - January 1, 2008 Category: Molecular Biology Authors: Jin T, Sui JL, Rosenhouse-Dantsker A, Chan KW, Jan LY, Logothetis DE Tags: Channels (Austin) Source Type: journals

Time course and specificity of the pharmacological disruption of the trafficking of voltage-gated calcium channels by gabapentin.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The mechanism of action of gabapentin is still not well understood. It binds to the alpha(2)delta-1 and alpha(2)delta-2 subunits of voltage-gated calcium channels but has little acute effect on calcium currents in several systems. However, our recent results conclusively demonstrated that gabapentin inhibited calcium currents when applied chronically but not acutely, both in heterologous expression systems and in dorsal root ganglion neurons.(1) In that study we only examined a 40-hour time point of incubation with gabapentin, and here we have extended these results to include the effect of up to 6 and 20 hours incubat...
Source: Channels - January 1, 2008 Category: Molecular Biology Authors: Heblich F, Tran Van Minh A, Hendrich J, Watschinger K, Dolphin AC Tags: Channels (Austin) Source Type: journals

Mutations within the agonist-binding site convert the homomeric alpha1 glycine receptor into a Zn2+-activated chloride channel.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The divalent cation Zn2+ has been shown to regulate inhibitory neurotransmission in the mammalian CNS by affecting the activation of the strychnine-sensitive glycine receptor (GlyR). In spinal neurons and cells expressing recombinant GlyRs, low micromolar (<10 microM) concentrations of Zn2+ enhance glycine currents, whereas higher concentrations (>10 microM) have an inhibitory effect. Mutational studies have localized the Zn2+ binding sites mediating allosteric potentiation and inhibition of GlyRs in distinct regions of the N-terminal extracellular domain of the GlyR alpha-subunits. Here, we examined the Zn2+ sen...
Source: Channels - January 1, 2008 Category: Molecular Biology Authors: Grudzinska J, Schumann T, Schemm R, Betz H, Laube B Tags: Channels (Austin) Source Type: journals

Differential effects of paramyotonia congenita mutations F1473S and F1705I on sodium channel gating.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We investigated effects of paramyotonia congenita mutations F1473S and F1705I on gating of skeletal muscle Na+ channels. We used on-cell recordings from Xenopus oocytes to compare fast inactivation and deactivation in wild-type and mutant channels. Then, we used gating current recordings to determine how these actions of PC mutants might be reflected in their effects on charge movement and its immobilization. F1473S, but not F1705I, accelerated deactivation from the inactivated state and enhanced the remobilization of gating charge. F1473S and F1705I decreased the completion of closed-state fast inactivation, and decre...
Source: Channels - January 1, 2008 Category: Molecular Biology Authors: Groome JR, Larsen MF, Coonts A Tags: Channels (Austin) Source Type: journals

Random assembly of SUR subunits in K(ATP) channel complexes.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Sulfonylurea receptors (SURs) associate with Kir6.x subunits to form tetradimeric K(ATP) channel complexes. SUR1 and SUR2 confer differential channel sensitivities to nucleotides and pharmacological agents, and are expressed in specific, but overlapping, tissues. This raises the question of whether these different SUR subtypes can assemble in the same channel complex and generate channels with hybrid properties. To test this, we engineered dimeric constructs of wild type or N160D mutant Kir6.2 fused to SUR1 or SUR2A. Dimeric fusions formed functional, ATP-sensitive, channels. Coexpression of weakly rectifying SUR1-Kir6...
Source: Channels - January 1, 2008 Category: Molecular Biology Authors: Cheng WW, Tong A, Flagg TP, Nichols CG Tags: Channels (Austin) Source Type: journals