Abstract
A-type voltage-gated potassium (Kv) channels are major regulators of neuronal excitability that have been mainly characterized in the central nervous system. By contrast, there is a paucity of knowledge about the molecular physiology of these Kv channels in the peripheral nervous system, including highly specialized and heterogenous dorsal root ganglion (DRG) neurons. Although all A-type Kv channels display pore-forming subunits with similar structural properties and fast inactivation, their voltage-, and time-dependent properties and modulation are significantly different. These differences ultimately determine distinct physiological roles of diverse A-type Kv channels, and how their dysfunction might contribute to neurological disorders. The importance of A-type Kv channels in DRG neurons is highlighted by recent studies that have linked their dysfunction to persistent pain sensitization. Here, we review the molecular neurophysiology of A-type Kv channels with an emphasis on those that have been identified and investigated in DRG nociceptors (Kv1.4, Kv3.4, and Kv4s). Also, we discuss evidence implicating these Kv channels in neuropathic pain resulting from injury, and present a perspective of outstanding challenges that must be tackled in order to discover novel treatments for intractable pain disorders.
Highlights
Inactivating voltage-gated K+ (Kv) currents were first characterized in neurons from the marine gastropod Onichidium verruculatum and were subsequently described as “A-type” (Hagiwara et al, 1961; Nakajima, 1966; Connor and Stevens, 1971a,b; Neher, 1971)
This article attempts to fill this gap by reviewing original discoveries in this area including recent studies demonstrating the physiological and molecular properties of A-type Kv channels in the pain pathway and how their dysfunction might contribute to pathological pain states
dorsal root ganglion (DRG) neurons express a variety of A-type Kv channels that regulate membrane excitability
Summary
Inactivating voltage-gated K+ (Kv) currents were first characterized in neurons from the marine gastropod Onichidium verruculatum and were subsequently described as “A-type” (Hagiwara et al, 1961; Nakajima, 1966; Connor and Stevens, 1971a,b; Neher, 1971). This article attempts to fill this gap by reviewing original discoveries in this area including recent studies demonstrating the physiological and molecular properties of A-type Kv channels in the pain pathway and how their dysfunction might contribute to pathological pain states This knowledge would stimulate further work to better understand these ion channels and help identify viable therapeutic interventions to treat pain disorders. The neuronal Kv4.1, Kv4.2, and Kv4.3 channels underlie lowvoltage activating A-type Kv currents, mainly expressed in somatodendritic compartments (Birnbaum et al, 2004; Jerng et al, 2004; Shah et al, 2010; Carrasquillo and Nerbonne, 2014) They are only modestly sensitive to 4-aminopyridine and highly insensitive to TEA.
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