IUPHAR/BPS guide to pharmacology CITE, Apr 26, 2023
The 6TM family of K channels comprises the voltage-gated K V subfamilies, the EAG subfamily (whic... more The 6TM family of K channels comprises the voltage-gated K V subfamilies, the EAG subfamily (which includes hERG channels), the Ca 2+ -activated Slo subfamily (actually with 7TM, termed BK) and the Ca 2+activated SK subfamily. These channels possess a pore-forming α subunit that comprise tetramers of identical subunits (homomeric) or of different subunits (heteromeric). Heteromeric channels can only be formed within subfamilies (e.g. K v 1.1 with K v 1.2; K v 7.2 with K v 7.3). The pharmacology largely reflects the subunit composition of the functional channel.K v 7 channelsK v 7.1-K v 7.5 (KCNQ1-5) K + channels are voltagegated K + channels with major roles in neurons, muscle cells and epithelia where they underlie physiologically important K + currents, such as the neuronal M-current and the cardiac IKs. Genetic deficiencies in all five KCNQ genes result in human excitability disorders, including epilepsy, autism spectrum disorders, cardiac arrhythmias and deafness. Thanks to the recent knowledge of the structure and function of human KCNQ-encoded proteins, these channels are increasingly used as drug targets for treating diseases . This is a citation summary for Voltage-gated potassium channels (K v ) in the Guide to Pharmacology database (GtoPdb). It exists purely as an adjunct to the database to facilitate the recognition of citations to and from the database by citation analyzers. Readers will almost certainly want to visit the relevant sections of the database which are given here under database links. GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts. For further details see [77]. Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators. Voltage-gated potassium channels (K v ) Introduction to Voltage-gated potassium channels (K v )
Voltage-gated K(+) channels containing pore-forming subunits of the Kv3 subfamily have specific r... more Voltage-gated K(+) channels containing pore-forming subunits of the Kv3 subfamily have specific roles in the fast repolarization of action potentials and enable neurons to fire repetitively at high frequencies. Each of the four known Kv3 genes encode multiple products by alternative splicing of 3' ends resulting in the expression of K(+) channel subunits differing only in their C-terminal sequence. The alternative splicing does not affect the electrophysiological properties of the channels, and its physiological role is unknown. It has been proposed that one of the functions of the alternative splicing of Kv3 genes is to produce subunit isoforms with differential subcellular membrane localizations in neurons and differential modulation by signaling pathways. We investigated the role of the alternative splicing of Kv3 subunits in subcellular localization by examining the brain distribution of the two alternatively spliced versions of the Kv3.1 gene (Kv3.1a and Kv3.1b) with antibo...
This selectivity is governed by direction-selective inhibition from starburst amacrine cells occu... more This selectivity is governed by direction-selective inhibition from starburst amacrine cells occurring during stimulus movement in the opposite or null direction. To understand the intrinsic membrane properties of starburst cells responsible for direction-selective GABA release, we performed whole-cell recordings from starburst cells in mouse retina. Voltage-clamp recordings revealed prominent voltagedependent K ϩ currents. The currents were mostly blocked by 1 mM TEA, activated rapidly at voltages more positive than Ϫ20 mV, and deactivated quickly, properties reminiscent of the currents carried by the Kv3 subfamily of K ϩ channels. Immunoblots confirmed the presence of Kv3.1 and Kv3.2 proteins in retina and immunohistochemistry revealed their expression in starburst cell somata and dendrites. The Kv3-like current in starburst cells was absent in Kv3.1-Kv3.2 knock-out mice. Current-clamp recordings showed that the fast activation of the Kv3 channels provides a voltage-dependent shunt that limits depolarization of the soma to potentials more positive than Ϫ20 mV. This provides a mechanism likely to contribute to the electrical isolation of individual starburst cell dendrites, a property thought essential for direction selectivity. This function of Kv3 channels differs from that in other neurons where they facilitate highfrequency repetitive firing. Moreover, we found a gradient in the intensity of Kv3.1b immunolabeling favoring proximal regions of starburst cells. We hypothesize that this Kv3 channel gradient contributes to the preference for centrifugal signal flow in dendrites underlying direction-selective GABA release from starburst amacrine cells
This summary article presents an overview of the molecular relationships among the voltage-gated ... more This summary article presents an overview of the molecular relationships among the voltage-gated potassium channels and a standard nomenclature for them, which is derived from the IUPHAR Compendium of Voltage-Gated Ion Channels. 1 The complete Compendium, including data tables for each member of the potassium channel family can be found at <http://www.iuphar-db.org/iuphar-ic/>. Almost a decade ago, a standardized nomenclature for the six-transmembrane domain (TM), voltage-gated K ϩ channel genes-the K V naming system-was widely adopted . This nomenclature was based on deduced phylogenetic relationships; channels that shared 65% sequence identity being assigned to one subfamily. A parallel nomenclature-KCN-was developed by the Human Genome Organisation (HUGO) . Since then, the K ϩ channel superfamily of genes has greatly expanded, requiring an update of the naming system.
The signaling properties of thalamocortical (TC) neurons depend on the diversity of ion conductan... more The signaling properties of thalamocortical (TC) neurons depend on the diversity of ion conductance mechanisms that underlie their rich membrane behavior at subthreshold potentials. Using patch-clamp recordings of TC neurons in brain slices from mice and a realistic conductance-based computational model, we characterized seven subthreshold ion currents of TC neurons and quantified their individual contributions to the total steady-state conductance at levels below tonic firing threshold. We then used the TC neuron model to show that the resting membrane potential results from the interplay of several inward and outward currents over a background provided by the potassium and sodium leak currents. The steady-state conductances of depolarizing Ih (hyperpolarization-activated cationic current), IT (low-threshold calcium current), and INaP (persistent sodium current) move the membrane potential away from the reversal potential of the leak conductances. This depolarization is counteracted in turn by the hyperpolarizing steady-state current of IA (fast transient A-type potassium current) and IKir (inwardly rectifying potassium current). Using the computational model, we have shown that single parameter variations compatible with physiological or pathological modulation promote burst firing periodicity. The balance between three amplifying variables (activation of IT, activation of INaP, and activation of IKir) and three recovering variables (inactivation of IT, activation of IA, and activation of Ih) determines the propensity, or lack thereof, of repetitive burst firing of TC neurons. We also have determined the specific roles that each of these variables have during the intrinsic oscillation.
The activation of T-lymphocytes is dependent upon, and accompanied by, an increase in voltage-gat... more The activation of T-lymphocytes is dependent upon, and accompanied by, an increase in voltage-gated K ؉ conductance. Kv1.3, a Shaker family K ؉ channel protein, appears to play an essential role in the activation of peripheral human T cells. Although Kv1.3-mediated K ؉ currents increase markedly during the activation process in mice, and to a lesser degree in humans, Kv1.3 mRNA levels in these organisms do not, indicating posttranscriptional regulation. In other tissues Shaker K ؉ channel proteins physically associate with cytoplasmic -subunits (Kv1-3). Recently it has been shown that Kv1 and Kv2 are expressed in mouse T cells and that they are up-regulated during mitogen-stimulated activation. In this study, we show that the human Kv subunits substantially increase K ؉ current amplitudes when coexpressed with their Kv1.3 counterpart, and that unlike in mouse, protein levels of human Kv2 remain constant upon activation. Differences in Kv2 expression between mice and humans may explain the differential K ؉ conductance increases which accompany T-cell proliferation in these organisms.
Mammalian voltage-activated Shaker K ÷ channels associate with at least three cytoplasmic protein... more Mammalian voltage-activated Shaker K ÷ channels associate with at least three cytoplasmic proteins: Kv101, Kv102 and Kv103. These/3 subnunits contain variable N-termini, which can modulate the inactivation of Shaker ct subunits, but are homologous throughout an aldo-keto reductase core. Human and ferret 133 proteins are identical with rat 101 throughout the core while 102 proteins are not; 102 also contains a shorter N-terminus and has no reported physiological role. We report that human 101 and 103 are derived from the same gene and that 102 modulates the inactivation properties of Kvl.4 ~ subunits.
An understanding of the diversity of cortical GABAergic interneurons is critical to understand th... more An understanding of the diversity of cortical GABAergic interneurons is critical to understand the function of the cerebral cortex. Recent data suggest that neurons expressing three markers, the Ca2+-binding protein parvalbumin (PV), the neuropeptide somatostatin (SST), and the ionotropic serotonin receptor 5HT3a (5HT3aR) account for nearly 100% of neocortical interneurons. Interneurons expressing each of these markers have a different embryological origin. Each group includes several types of interneurons that differ in morphological and electrophysiological properties and likely have different functions in the cortical circuit. The PV group accounts for *40% of GABAergic neurons and includes fast spiking basket cells and chandelier cells. The SST group, which represents *30% of GABAergic neurons, includes the Martinotti cells and a set of neurons that specifically target layer IV. The 5HT3aR group, which also accounts for *30% of the total interneuronal population, is heterogeneous and includes all of the neurons that express the neuropeptide VIP, as well as an equally numerous subgroup of neurons that do not express VIP and includes neurogliaform cells. The universal modulation of these neurons by serotonin and acetylcholine via ionotropic receptors suggests that they might be involved in shaping cortical circuits during specific brain states and behavioral contexts. Wiley Periodicals, Inc. Develop Neurobiol 71: 45-61, 2011
Voltage-gated potassium channels constitute the largest group of heteromeric ion channels discove... more Voltage-gated potassium channels constitute the largest group of heteromeric ion channels discovered to date. Over 20 genes have been isolated, encoding different channel subunit proteins which form functional tetrameric K+ channels. We have analyzed the subcellular localization of subunit Kv3.1b, a member of the Kv3 (Shaw-like) subfamily, in rat brain at the light and electron microscopic level, using immunocytochemical detection. Detailed localization was carried out in specific neurons of the neocortex, hippocampus and cerebellum. The identity of Kv3.1b-positive neurons was established using double labeling with markers for specific neuronal populations. In the neocortex, the Kv3.1b subunit was expressed in most parvalbumin-containing bipolar, basket or chandelier cells, and in some bipolar or double bouquet neurons containing calbindin. In the hippocampus, Kv3.1b was expressed in many parvalbumin-containing basket cells, as well as in calbindin-positive neurons in the stratum oriens, and in a small number of interneurons that did not stain for either parvalbumin or calbindin. Kv3.1b protein was not present in pyramidal cells in the neocortex and the hippocampus, but these cells were outlined by labeled presynaptic terminals from interneuron axons that surround the postsynaptic cell. In the cerebellar cortex, granule cells were the only population expressing the channel protein. Careful examination of individual granule cells revealed a non-uniform distribution of Kv3.1 staining on the somata: circular bands of labeling were present in the vicinity of the axon hillock. In cortical and hippocampal interneurons, as well as in cerebellar granule cells, the Kv3.1b subunit was present in somatic and unmyelinated axonal membranes and adjacent cytoplasm, as well as in the most proximal portion of dendritic processes, but not throughout most of the dendrite. Labeling was also seen in the terminals of labeled axons, but not at a higher concentration than in other parts of the axon. The distribution in the cells analyzed supports a role in action potential transmission by regulating action potential duration.
Rudy. Kv3.1-Kv3.2 channels underlie a high-voltage-activating component of the delayed rectifier ... more Rudy. Kv3.1-Kv3.2 channels underlie a high-voltage-activating component of the delayed rectifier K ϩ current in projecting neurons from the globus pallidus. J. Neurophysiol. 82: 1512Neurophysiol. 82: -1528Neurophysiol. 82: , 1999. The globus pallidus plays central roles in the basal ganglia circuitry involved in movement control as well as in cognitive and emotional functions. There is therefore great interest in the anatomic and electrophysiological characterization of this nucleus. Most pallidal neurons are GABAergic projecting cells, a large fraction of which express the calcium binding protein parvalbumin (PV). Here we show that PVcontaining pallidal neurons coexpress Kv3.1 and Kv3.2 K ϩ channel proteins and that both Kv3.1 and Kv3.2 antibodies coprecipitate both channel proteins from pallidal membrane extracts solubilized with nondenaturing detergents, suggesting that the two channel subunits are forming heteromeric channels. Kv3.1 and Kv3.2 channels have several unusual electrophysiological properties when expressed in heterologous expression systems and are thought to play special roles in neuronal excitability including facilitating sustained high-frequency firing in fast-spiking neurons such as interneurons in the cortex and the hippocampus. Electrophysiological analysis of freshly dissociated pallidal neurons demonstrates that these cells have a current that is nearly identical to the currents expressed by Kv3.1 and Kv3.2 proteins in heterologous expression systems, including activation at very depolarized membrane potentials (more positive than Ϫ10 mV) and very fast deactivation rates. These results suggest that the electrophysiological properties of native channels containing Kv3.1 and Kv3.2 proteins in pallidal neurons are not significantly affected by factors such as associated subunits or postranslational modifications that result in channels having different properties in heterologous expression systems and native neurons. Most neurons in the globus pallidus have been reported to fire sustained trains of action potentials at high-frequency. Kv3.1-Kv3.2 voltage-gated K ϩ channels may play a role in helping maintain sustained high-frequency repetitive firing as they probably do in other neurons.
Article, publication date, and citation information can be found at http://pharmrev.aspetjournals... more Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org.
IUPHAR/BPS guide to pharmacology CITE, Apr 26, 2023
The 6TM family of K channels comprises the voltage-gated K V subfamilies, the EAG subfamily (whic... more The 6TM family of K channels comprises the voltage-gated K V subfamilies, the EAG subfamily (which includes hERG channels), the Ca 2+ -activated Slo subfamily (actually with 7TM, termed BK) and the Ca 2+activated SK subfamily. These channels possess a pore-forming α subunit that comprise tetramers of identical subunits (homomeric) or of different subunits (heteromeric). Heteromeric channels can only be formed within subfamilies (e.g. K v 1.1 with K v 1.2; K v 7.2 with K v 7.3). The pharmacology largely reflects the subunit composition of the functional channel.K v 7 channelsK v 7.1-K v 7.5 (KCNQ1-5) K + channels are voltagegated K + channels with major roles in neurons, muscle cells and epithelia where they underlie physiologically important K + currents, such as the neuronal M-current and the cardiac IKs. Genetic deficiencies in all five KCNQ genes result in human excitability disorders, including epilepsy, autism spectrum disorders, cardiac arrhythmias and deafness. Thanks to the recent knowledge of the structure and function of human KCNQ-encoded proteins, these channels are increasingly used as drug targets for treating diseases . This is a citation summary for Voltage-gated potassium channels (K v ) in the Guide to Pharmacology database (GtoPdb). It exists purely as an adjunct to the database to facilitate the recognition of citations to and from the database by citation analyzers. Readers will almost certainly want to visit the relevant sections of the database which are given here under database links. GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts. For further details see [77]. Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators. Voltage-gated potassium channels (K v ) Introduction to Voltage-gated potassium channels (K v )
Voltage-gated K(+) channels containing pore-forming subunits of the Kv3 subfamily have specific r... more Voltage-gated K(+) channels containing pore-forming subunits of the Kv3 subfamily have specific roles in the fast repolarization of action potentials and enable neurons to fire repetitively at high frequencies. Each of the four known Kv3 genes encode multiple products by alternative splicing of 3' ends resulting in the expression of K(+) channel subunits differing only in their C-terminal sequence. The alternative splicing does not affect the electrophysiological properties of the channels, and its physiological role is unknown. It has been proposed that one of the functions of the alternative splicing of Kv3 genes is to produce subunit isoforms with differential subcellular membrane localizations in neurons and differential modulation by signaling pathways. We investigated the role of the alternative splicing of Kv3 subunits in subcellular localization by examining the brain distribution of the two alternatively spliced versions of the Kv3.1 gene (Kv3.1a and Kv3.1b) with antibo...
This selectivity is governed by direction-selective inhibition from starburst amacrine cells occu... more This selectivity is governed by direction-selective inhibition from starburst amacrine cells occurring during stimulus movement in the opposite or null direction. To understand the intrinsic membrane properties of starburst cells responsible for direction-selective GABA release, we performed whole-cell recordings from starburst cells in mouse retina. Voltage-clamp recordings revealed prominent voltagedependent K ϩ currents. The currents were mostly blocked by 1 mM TEA, activated rapidly at voltages more positive than Ϫ20 mV, and deactivated quickly, properties reminiscent of the currents carried by the Kv3 subfamily of K ϩ channels. Immunoblots confirmed the presence of Kv3.1 and Kv3.2 proteins in retina and immunohistochemistry revealed their expression in starburst cell somata and dendrites. The Kv3-like current in starburst cells was absent in Kv3.1-Kv3.2 knock-out mice. Current-clamp recordings showed that the fast activation of the Kv3 channels provides a voltage-dependent shunt that limits depolarization of the soma to potentials more positive than Ϫ20 mV. This provides a mechanism likely to contribute to the electrical isolation of individual starburst cell dendrites, a property thought essential for direction selectivity. This function of Kv3 channels differs from that in other neurons where they facilitate highfrequency repetitive firing. Moreover, we found a gradient in the intensity of Kv3.1b immunolabeling favoring proximal regions of starburst cells. We hypothesize that this Kv3 channel gradient contributes to the preference for centrifugal signal flow in dendrites underlying direction-selective GABA release from starburst amacrine cells
This summary article presents an overview of the molecular relationships among the voltage-gated ... more This summary article presents an overview of the molecular relationships among the voltage-gated potassium channels and a standard nomenclature for them, which is derived from the IUPHAR Compendium of Voltage-Gated Ion Channels. 1 The complete Compendium, including data tables for each member of the potassium channel family can be found at <http://www.iuphar-db.org/iuphar-ic/>. Almost a decade ago, a standardized nomenclature for the six-transmembrane domain (TM), voltage-gated K ϩ channel genes-the K V naming system-was widely adopted . This nomenclature was based on deduced phylogenetic relationships; channels that shared 65% sequence identity being assigned to one subfamily. A parallel nomenclature-KCN-was developed by the Human Genome Organisation (HUGO) . Since then, the K ϩ channel superfamily of genes has greatly expanded, requiring an update of the naming system.
The signaling properties of thalamocortical (TC) neurons depend on the diversity of ion conductan... more The signaling properties of thalamocortical (TC) neurons depend on the diversity of ion conductance mechanisms that underlie their rich membrane behavior at subthreshold potentials. Using patch-clamp recordings of TC neurons in brain slices from mice and a realistic conductance-based computational model, we characterized seven subthreshold ion currents of TC neurons and quantified their individual contributions to the total steady-state conductance at levels below tonic firing threshold. We then used the TC neuron model to show that the resting membrane potential results from the interplay of several inward and outward currents over a background provided by the potassium and sodium leak currents. The steady-state conductances of depolarizing Ih (hyperpolarization-activated cationic current), IT (low-threshold calcium current), and INaP (persistent sodium current) move the membrane potential away from the reversal potential of the leak conductances. This depolarization is counteracted in turn by the hyperpolarizing steady-state current of IA (fast transient A-type potassium current) and IKir (inwardly rectifying potassium current). Using the computational model, we have shown that single parameter variations compatible with physiological or pathological modulation promote burst firing periodicity. The balance between three amplifying variables (activation of IT, activation of INaP, and activation of IKir) and three recovering variables (inactivation of IT, activation of IA, and activation of Ih) determines the propensity, or lack thereof, of repetitive burst firing of TC neurons. We also have determined the specific roles that each of these variables have during the intrinsic oscillation.
The activation of T-lymphocytes is dependent upon, and accompanied by, an increase in voltage-gat... more The activation of T-lymphocytes is dependent upon, and accompanied by, an increase in voltage-gated K ؉ conductance. Kv1.3, a Shaker family K ؉ channel protein, appears to play an essential role in the activation of peripheral human T cells. Although Kv1.3-mediated K ؉ currents increase markedly during the activation process in mice, and to a lesser degree in humans, Kv1.3 mRNA levels in these organisms do not, indicating posttranscriptional regulation. In other tissues Shaker K ؉ channel proteins physically associate with cytoplasmic -subunits (Kv1-3). Recently it has been shown that Kv1 and Kv2 are expressed in mouse T cells and that they are up-regulated during mitogen-stimulated activation. In this study, we show that the human Kv subunits substantially increase K ؉ current amplitudes when coexpressed with their Kv1.3 counterpart, and that unlike in mouse, protein levels of human Kv2 remain constant upon activation. Differences in Kv2 expression between mice and humans may explain the differential K ؉ conductance increases which accompany T-cell proliferation in these organisms.
Mammalian voltage-activated Shaker K ÷ channels associate with at least three cytoplasmic protein... more Mammalian voltage-activated Shaker K ÷ channels associate with at least three cytoplasmic proteins: Kv101, Kv102 and Kv103. These/3 subnunits contain variable N-termini, which can modulate the inactivation of Shaker ct subunits, but are homologous throughout an aldo-keto reductase core. Human and ferret 133 proteins are identical with rat 101 throughout the core while 102 proteins are not; 102 also contains a shorter N-terminus and has no reported physiological role. We report that human 101 and 103 are derived from the same gene and that 102 modulates the inactivation properties of Kvl.4 ~ subunits.
An understanding of the diversity of cortical GABAergic interneurons is critical to understand th... more An understanding of the diversity of cortical GABAergic interneurons is critical to understand the function of the cerebral cortex. Recent data suggest that neurons expressing three markers, the Ca2+-binding protein parvalbumin (PV), the neuropeptide somatostatin (SST), and the ionotropic serotonin receptor 5HT3a (5HT3aR) account for nearly 100% of neocortical interneurons. Interneurons expressing each of these markers have a different embryological origin. Each group includes several types of interneurons that differ in morphological and electrophysiological properties and likely have different functions in the cortical circuit. The PV group accounts for *40% of GABAergic neurons and includes fast spiking basket cells and chandelier cells. The SST group, which represents *30% of GABAergic neurons, includes the Martinotti cells and a set of neurons that specifically target layer IV. The 5HT3aR group, which also accounts for *30% of the total interneuronal population, is heterogeneous and includes all of the neurons that express the neuropeptide VIP, as well as an equally numerous subgroup of neurons that do not express VIP and includes neurogliaform cells. The universal modulation of these neurons by serotonin and acetylcholine via ionotropic receptors suggests that they might be involved in shaping cortical circuits during specific brain states and behavioral contexts. Wiley Periodicals, Inc. Develop Neurobiol 71: 45-61, 2011
Voltage-gated potassium channels constitute the largest group of heteromeric ion channels discove... more Voltage-gated potassium channels constitute the largest group of heteromeric ion channels discovered to date. Over 20 genes have been isolated, encoding different channel subunit proteins which form functional tetrameric K+ channels. We have analyzed the subcellular localization of subunit Kv3.1b, a member of the Kv3 (Shaw-like) subfamily, in rat brain at the light and electron microscopic level, using immunocytochemical detection. Detailed localization was carried out in specific neurons of the neocortex, hippocampus and cerebellum. The identity of Kv3.1b-positive neurons was established using double labeling with markers for specific neuronal populations. In the neocortex, the Kv3.1b subunit was expressed in most parvalbumin-containing bipolar, basket or chandelier cells, and in some bipolar or double bouquet neurons containing calbindin. In the hippocampus, Kv3.1b was expressed in many parvalbumin-containing basket cells, as well as in calbindin-positive neurons in the stratum oriens, and in a small number of interneurons that did not stain for either parvalbumin or calbindin. Kv3.1b protein was not present in pyramidal cells in the neocortex and the hippocampus, but these cells were outlined by labeled presynaptic terminals from interneuron axons that surround the postsynaptic cell. In the cerebellar cortex, granule cells were the only population expressing the channel protein. Careful examination of individual granule cells revealed a non-uniform distribution of Kv3.1 staining on the somata: circular bands of labeling were present in the vicinity of the axon hillock. In cortical and hippocampal interneurons, as well as in cerebellar granule cells, the Kv3.1b subunit was present in somatic and unmyelinated axonal membranes and adjacent cytoplasm, as well as in the most proximal portion of dendritic processes, but not throughout most of the dendrite. Labeling was also seen in the terminals of labeled axons, but not at a higher concentration than in other parts of the axon. The distribution in the cells analyzed supports a role in action potential transmission by regulating action potential duration.
Rudy. Kv3.1-Kv3.2 channels underlie a high-voltage-activating component of the delayed rectifier ... more Rudy. Kv3.1-Kv3.2 channels underlie a high-voltage-activating component of the delayed rectifier K ϩ current in projecting neurons from the globus pallidus. J. Neurophysiol. 82: 1512Neurophysiol. 82: -1528Neurophysiol. 82: , 1999. The globus pallidus plays central roles in the basal ganglia circuitry involved in movement control as well as in cognitive and emotional functions. There is therefore great interest in the anatomic and electrophysiological characterization of this nucleus. Most pallidal neurons are GABAergic projecting cells, a large fraction of which express the calcium binding protein parvalbumin (PV). Here we show that PVcontaining pallidal neurons coexpress Kv3.1 and Kv3.2 K ϩ channel proteins and that both Kv3.1 and Kv3.2 antibodies coprecipitate both channel proteins from pallidal membrane extracts solubilized with nondenaturing detergents, suggesting that the two channel subunits are forming heteromeric channels. Kv3.1 and Kv3.2 channels have several unusual electrophysiological properties when expressed in heterologous expression systems and are thought to play special roles in neuronal excitability including facilitating sustained high-frequency firing in fast-spiking neurons such as interneurons in the cortex and the hippocampus. Electrophysiological analysis of freshly dissociated pallidal neurons demonstrates that these cells have a current that is nearly identical to the currents expressed by Kv3.1 and Kv3.2 proteins in heterologous expression systems, including activation at very depolarized membrane potentials (more positive than Ϫ10 mV) and very fast deactivation rates. These results suggest that the electrophysiological properties of native channels containing Kv3.1 and Kv3.2 proteins in pallidal neurons are not significantly affected by factors such as associated subunits or postranslational modifications that result in channels having different properties in heterologous expression systems and native neurons. Most neurons in the globus pallidus have been reported to fire sustained trains of action potentials at high-frequency. Kv3.1-Kv3.2 voltage-gated K ϩ channels may play a role in helping maintain sustained high-frequency repetitive firing as they probably do in other neurons.
Article, publication date, and citation information can be found at http://pharmrev.aspetjournals... more Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org.
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