Distinct potassium channels on pain-sensing neurons

M Rasband

E Park

T Vanderah

J Lai

F Porreca

J Trimmer

^{Department of Biochemistry and Cell Biology, State University of New York, Stony Brook, NY 11794; and}^{Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724}

^{To whom reprint requests should be addressed at: Department of Biochemistry, State University of New York, Stony Brook, NY 11794-5215. E-mail:}ude.bsynus@remmirt.semaj.

Edited by Lily Y. Jan, University of California, San Francisco, CA, and approved September 5, 2001

Received 2001 Jul 19

Abstract

Differential expression of ion channels contributes functional diversity to sensory neuron signaling. We find nerve injury induced by the Chung model of neuropathic pain leads to striking reductions in voltage-gated K^{(Kv) channel subunit expression in dorsal root ganglia (DRG) neurons, suggesting a potential molecular mechanism for hyperexcitability of injured nerves. Moreover, specific classes of DRG neurons express distinct Kv channel subunit combinations. Importantly, Kv1.4 is the sole Kv1 α subunit expressed in smaller diameter neurons, suggesting that homomeric Kv1.4 channels predominate in Aδ and C fibers arising from these cells. These neurons are presumably nociceptors, because they also express the VR-1 capsaicin receptor, calcitonin gene-related peptide, and/or Na}^{channel SNS/PN3/Nav1.8. In contrast, larger diameter neurons associated with mechanoreception and proprioception express high levels of Kv1.1 and Kv1.2 without Kv1.4 or other Kv1 α subunits, suggesting that heteromers of these subunits predominate on large, myelinated afferent axons that extend from these cells.}

Abstract

In the peripheral nervous system (PNS), sensory neuron cell bodies reside in dorsal root ganglia (DRG), and extend axons that innervate both peripheral and central targets. A diverse group of ligand- and voltage-gated ion channels transduce innocuous and noxious (nociceptive) stimuli into depolarizations that are conducted along axons and finally converted into neurotransmitter release. For example, nociceptive neurons express specific ion channels [ATP-gated channels, voltage-gated Na^{channels (NaChs), H}^{-gated channels, and capsaicin receptor channels] that represent attractive targets for therapeutic intervention of peripheral pain (}1). Little is known of the molecular identity of the voltage-gated K^{(Kv) channels that regulate membrane repolarization, resting membrane potential, frequency of firing, and neurotransmitter release in sensory neurons. Mammalian}Shaker-related or Kv1 proteins are composed of four transmembrane α subunits (2–4), and up to four modulatory cytoplasmic Kvβ subunits (5, 6).

The predominant Kv1 channels in myelinated nerve fibers comprise coassembled Kv1.1, Kv1.2, and Kvβ2.1 (7–9) that would form dendrotoxin (DTX)-sensitive delayed-rectifier channels as Kv1.1, Kv1.2 and Kv1.6 are DTX-sensitive. DTX-sensitive transient or A-type channels in unmyelinated axons of many central neurons consist of Kv1.1 and/or Kv1.2 coassembled with Kv1.4 (10–12). Distinct populations of defined DRG neurons express a variety of Kv currents whose pharmacological blockade affects neuronal excitability (13–16). Nerve injury results in reductions in Kv currents, hyperexcitability, and hyperalgesia (17). To better understand the molecular physiology and pharmacology of sensory neurons, and to identify specific Kv channels that may represent potential targets for therapeutics to treat peripheral pain, we investigated Kv1 subunit expression in mammalian DRG before and after nerve injury.

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Acknowledgments

We thank Dr. Louis Manganas for providing transfected COS-1 cell lysates, Dr. Gail Mandel for critical reading of the manuscript, and Chris LaBianca for technical assistance. Supported by National Institutes of Health Grants NS34383 and NS10906, and by Spinal Cord Research Foundation Grant 2040.

Acknowledgments

Abbreviations

DRG	dorsal root ganglia
CGRP	calcitonin gene-related peptide
Kv	voltage-gated K⁺
NaChs	voltage-gated Na^channels
DTX	dendrotoxin
NF-M	Neurofilament-M

Abbreviations

Footnotes

This paper was submitted directly (Track II) to the PNAS office.

Footnotes

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