International Union of Pharmacology. LIII. Nomenclature and Molecular Relationships of Voltage-Gated Potassium Channels

Gutman, George A.; Chandy, K. George; Grissmer, Stephan; Lazdunski, Michel; McKinnon, David; Pardo, Luis A.; Robertson, Gail A.; Rudy, Bernardo; Sanguinetti, Michael C.; Stühmer, Walter; Wang, Xiaoliang

doi:10.1124/pr.57.4.10

Cited by 780 publications

(746 citation statements)

References 18 publications

Supporting

Mentioning

708

Contrasting

Unclassified

Order By: Relevance

“…It is not entirely clear that the Kv2 channels observed are represented solely by Kv2.1. However, Kv2.2 is also sensitive to stromatoxin and displays IC 50 values for inhibition by TEA and 4-aminopyridine that are closer (∼1 mmol/l) to the values reported here [24]. Functional Kv channels are often heterotetramers, and the native alpha cell Kv2 channel may include Kv2.1 and Kv2.2 subunits, and possibly the Kv6.1 reported previously [9], as this subunit may also combine with Kv2 channels.…”

Section: Discussionsupporting

confidence: 77%

Voltage-dependent K+ channels are positive regulators of alpha cell action potential generation and glucagon secretion in mice and humans

2010

View full text Add to dashboard Cite

Aims/hypothesis The regulation of glucagon secretion from alpha cells is poorly understood. Since action potential firing at low glucose is required for glucagon secretion, we hypothesised that voltage-dependent K + (Kv) currents limit glucagon secretion under these conditions, similarly to their role in insulin secretion. Methods Kv currents and action potential firing of mouse and human alpha cells, identified by immunostaining, were examined by whole-cell patch-clamp. Glucagon secretion from mouse and human islets was measured by ELISA. Results Kv current density was 35% larger in alpha than in beta cells. Alpha cell Kv channels were sensitive to block by tetraethylammonium (TEA) and 4-aminopyridine. Surprisingly, Kv channel inhibition reduced glucagon release to the same extent as glucose. Robust action potential firing was observed in beta cells when ATP-sensitive K + channels were closed, but in alpha cells a negative current (−8 pA) injection was required for action potential firing. TEA (0.5 mmol/l) impaired alpha cell action potential firing, which could be restored by further hyperpolarising current injection (−16 pA). Kv currents were more sensitive to the Kv2 inhibitor stromatoxin (100 nmol/l) in mouse (80%) than in human (45%) alpha cells. Finally, the maxi-K (BK) channel inhibitor iberiotoxin (100 nmol/l) blocked 55% of the current in human alpha cells and inhibited glucagon release from human islets. Conclusions/interpretation Kv currents in alpha cells are positive regulators of glucagon secretion. These currents, mediated by Kv2 and BK channels, limit membrane depolarisation, and prevent inactivation of alpha cell action potentials and suppression of glucagon release.

show abstract

Section: Discussionsupporting

confidence: 77%

Voltage-dependent K+ channels are positive regulators of alpha cell action potential generation and glucagon secretion in mice and humans

2010

View full text Add to dashboard Cite

show abstract

“…The K v family has more than 40 members, 108 and the channels that they form include the delayedrectifier K ϩ current (I K ) responsible for the repolarization phase of action potentials, as well as other voltagegated K ϩ currents that have diverse functions in neurons, including the A-current (K v 1, K v 3, and K v 4) and the M-current (KCNQ).…”

Section: Voltage-gated Potassium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

View full text Add to dashboard Cite

Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

show abstract

“…Voltage-gated potassium channels (Kv channels) are the largest and most diverse group of the ion channels including up to 40 members [23]. They are composed of four, generally identical α-subunits, each of which is composed of six transmembrane domains (S1-S6) connected by extracellular and intracellular loops.…”

Section: Introductionmentioning

confidence: 99%

7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

Balajthy

Somodi

Pethő

et al. 2016

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

In vitro manipulation of membrane sterol level affects the regulation of ion channels and consequently certain cellular functions; however, a comprehensive study that confirms the pathophysiological significance of these results is missing. The malfunction of 7-dehydrocholesterol (7DHC) reductase in Smith-Lemli-Opitz syndrome (SLOS) leads to the elevation of the 7-dehydrocholesterol level in the plasma membrane. T lymphocytes were isolated from SLOS patients to assess the effect of the in vivo altered membrane sterol composition on the operation of the voltage-gated Kv1.3 channel and the ion channel-dependent mitogenic responses. We found that the kinetic and equilibrium parameters of Kv1.3 activation changed in SLOS cells. Identical changes in Kv1.3 operation were observed when control/healthy T cells were loaded with 7DHC. Removal of the putative sterol binding sites on Kv1.3 resulted in a phenotype that was not influenced by the elevation in membrane sterol level. Functional assays exhibited impaired activation and proliferation rate of T cells probably partially due to the modified Kv1.3 operation. We concluded that the altered membrane sterol composition hindered the operation of Kv1.3 as well as the ion channel-controlled T cell functions.

show abstract

International Union of Pharmacology. LIII. Nomenclature and Molecular Relationships of Voltage-Gated Potassium Channels

Cited by 780 publications

References 18 publications

Voltage-dependent K+ channels are positive regulators of alpha cell action potential generation and glucagon secretion in mice and humans

Voltage-dependent K+ channels are positive regulators of alpha cell action potential generation and glucagon secretion in mice and humans

Molecular Targets for Antiepileptic Drug Development

7DHC-induced changes of Kv1.3 operation contributes to modified T cell function in Smith-Lemli-Opitz syndrome

Contact Info

Product

Resources

About