Kv5, Kv6, Kv8, and Kv9 subunits: No simple silent bystanders

Bocksteins, Elke

doi:10.1085/jgp.201511507

Cited by 81 publications

(91 citation statements)

References 154 publications

(307 reference statements)

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“…Kv2.1 subunits have especially wide and high expression in many neuronal types. Of particular interest for possible drug development, Kv2 subunits can make heteromeric channels with subunits from other gene families, including Kv5, Kv6, Kv8, and Kv9 subunits, so-called “silent” subunits that seem not to make functional channels on their own 225,226 . In the context of pain, attention has focused particularly on Kv9.1 subunits, for which a common human allelic variant is strongly associated with increased susceptibility to neuropathic pain 7 .…”

Section: Ion Channels As Drug Targetsmentioning

confidence: 99%

Breaking barriers to novel analgesic drug development

Yekkirala

Roberson

Bean

et al. 2017

Nat Rev Drug Discov

285

246

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Acute and chronic pain complaints, while very common, are generally poorly served by existing therapies. The unmet clinical need reflects the failure in developing novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms coupled with the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities to develop new therapeutic strategies and revisit existing targets, including modulating ion channels, enzymes and GPCRs.

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Section: Ion Channels As Drug Targetsmentioning

confidence: 99%

Breaking barriers to novel analgesic drug development

Yekkirala

Roberson

Bean

et al. 2017

Nat Rev Drug Discov

285

246

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“…The Kv5‐Kv6 and Kv8‐Kv9 subfamilies are composed of γ subunits, which are electrically silent α subunits. These γ subunits do not form functional channels when expressed alone, but co‐assemble with Kv1‐4 channels (mainly with Kv2 α subunits) to form heteromultimeric channels with different kinetic and pharmacological properties, broadening the functional diversity of Kv channels in VSMCs . Members of the Kv7 channels subfamily ( KCNQ genes) contribute to VSMC hyperpolarization and vascular tone in several vascular beds .…”

Section: Vascular Smooth Muscle Cell Kv Channelsmentioning

confidence: 99%

Kv channels and vascular smooth muscle cell proliferation

2018

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Kv channels are present in virtually all VSMCs and strongly influence contractile responses. However, they are also instrumental in the proliferative, migratory, and secretory functions of synthetic, dedifferentiated VSMCs upon PM. In fact, Kv channels not only contribute to all these processes but also are active players in the phenotypic switch itself. This review is focused on the role(s) of Kv channels in VSMC proliferation, which is one of the best characterized functions of dedifferentiated VSMCs.VSMC proliferation is a complex process requiring specific Kv channels at specific time and locations. Their identification is further complicated by their large diversity and the differences in expression across vascular beds. Of interest, both conserved changes in some Kv channels and vascular bed-specific regulation of others seem to coexist and participate in VSMC proliferation through complementary mechanisms.Such a system will add flexibility to the process while providing the required robustness to preserve this fundamental cellular response. K E Y W O R D Scell cycle regulation, phenotypic modulation, potassium channels, vascular remodeling, vascular smooth muscle cell proliferation | THE MULTIPLE PHENOTYPES OF VASCULAR SMOOTH MUSCLE CELLSVSMCs in the vessel wall express a unique repertoire of contractile proteins, signaling molecules, receptors, and ion channels and exhibit extremely low rates of proliferation, migration, and production of ECM proteins. However, VSMCs maintain significant plasticity even in adult animal. In response to changes in environmental cues, VSMCs switch from their contractile, differentiated phenotype to a dedifferentiated, synthetic, and proliferative phenotype. This process, known as PM or phenotypic switching, entails profound structural and functional changes involving changes in gene expression and signaling mecha- 3-7The contractile state is controlled by multiple transcriptional factors, being SRF the best characterized. SRF binds to a specific cis-element, the CArG box, present in the promoter region of target genes. While most VSMC differentiation marker genes contain one or multiple CArG elements, CArG-SRF complexes can also modulate the expression of proliferation-related genes. 8,9 Specificity of these regulatory mechanisms depends on the expression of myocardin, a SRF coactivator expressed exclusively in SMCs and cardiomyocytes. 10-12Myocardin expression is dramatically reduced in cultured SMC, in contrast to the constant levels of SRF with SMC phenotypic modulation.Understanding myocardin function will permit to understand the normal VSMC differentiation and also PM.13

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“…For example, a mouse mutant of Kcnb1 presented defects in insulin secretion and rapid progression of induced seizures but did not exhibit spontaneous seizures that characterize most human KCNB1 mutants. Developmental disturbances of brain ventricles seen in Kcnb1‐deficient zebrafish were not observed in mouse mutants . Perhaps, different phenotypes could be attributed to differences in the distribution of bodily fluids in aquatic and terrestrial animals.…”

Section: Introductionmentioning

confidence: 94%

“…T1, N‐terminal tetramerization domain; P, pore domain; Kv2, Kv2 domain; CTA, C‐terminal activation domain. Figure based on References …”

Section: Structure Of Voltage‐gated Potassium Channelsmentioning

confidence: 99%

“…The KvS subunits (ie, Kv5 [Kcnf], Kv6 [Kcng], Kv8 [Kcnv], and Kv9 [Kcns]) do not form functional homotetrameric channels. They join electrically‐active α‐subunits (eg, Kcnb1) to form heterotetrameric KCNB1/KvS channels with variable content . Thus, it is unsurprising that each of these heterotetramers may have specific properties.…”

Section: Structure Of Voltage‐gated Potassium Channelsmentioning

confidence: 99%

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Kv2.1 voltage‐gated potassium channels in developmental perspective

Jędrychowska

Korzh

2019

Developmental Dynamics

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Kv2.1 voltage‐gated potassium channels consist of two types of α‐subunits: (a) electrically‐active Kcnb1 α‐subunits and (b) silent or modulatory α‐subunits plus β‐subunits that, similar to silent α‐subunits, also regulate electrically‐active subunits. Voltage‐gated potassium channels were traditionally viewed, mainly by electrophysiologists, as regulators of the electrical activity of the plasma membrane in excitable cells, a role that is performed by transmembrane protein domains of α‐subunits that form the electric pore. Genetic studies revealed a role for this region of α‐subunits of voltage‐gated potassium channels in human neurodevelopmental disorders, such as epileptic encephalopathy. The N‐ and C‐terminal domains of α‐subunits interact to form the cytoplasmic subunit of heterotetrameric potassium channels that regulate electric pores. Subsequent animal studies revealed the developmental functions of Kcnb1‐containing voltage‐gated potassium channels and illustrated their role during brain development and reproduction. These functions of potassium channels are discussed in this review in the context of regulatory interactions between electrically‐active and regulatory subunits.

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Kv5, Kv6, Kv8, and Kv9 subunits: No simple silent bystanders

Cited by 81 publications

References 154 publications

Breaking barriers to novel analgesic drug development

Breaking barriers to novel analgesic drug development

Kv channels and vascular smooth muscle cell proliferation

Kv2.1 voltage‐gated potassium channels in developmental perspective

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