Abstract
The dorsal root ganglion (DRG) contains heterogeneous populations of sensory neurons including primary nociceptive neurons and C-fibers implicated in pain signaling. Recent studies have demonstrated DRG hyperexcitability associated with downregulation of A-type K+ channels; however, the molecular correlate of the corresponding A-type K+ current (IA) has remained hypothetical. Kv4 channels may underlie the IA in DRG neurons. We combined electrophysiology, molecular biology (Whole-Tissue and Single-Cell RT-PCR) and immunohistochemistry to investigate the molecular basis of the IA in acutely dissociated DRG neurons from 7- to 8-day-old rats. Whole-cell recordings demonstrate a robust tetraethylammonium-resistant (20 mM) and 4-aminopyridine-sensitive (5 mM) IA. Matching Kv4 channel properties, activation and inactivation of this IA occur in the subthreshold range of membrane potentials and the rate of recovery from inactivation is rapid and voltage-dependent. Among Kv4 transcripts, the DRG expresses significant levels of Kv4.1 and Kv4.3 mRNAs. Also, single small-medium diameter DRG neurons (∼30 μm) exhibit correlated frequent expression of mRNAs encoding Kv4.1 and Nav1.8, a known nociceptor marker. In contrast, the expressions of Kv1.4 and Kv4.2 mRNAs at the whole-tissue and single-cell levels are relatively low and infrequent. Kv4 protein expression in nociceptive DRG neurons was confirmed by immunohistochemistry, which demonstrates colocalization of Kv4.3 and Nav1.8, and negligible expression of Kv4.2. Furthermore, specific dominant-negative suppression and overexpression strategies confirmed the contribution of Kv4 channels to IA in DRG neurons. Contrasting the expression patterns of Kv4 channels in the central and peripheral nervous systems, we discuss possible functional roles of these channels in primary sensory neurons.
Highlights
Voltage-gated potassium (Kv) channels are quintessential regulators of electrical excitability in the nervous system
ISOLATION AND CHARACTERIZATION OF A SUBTHRESHOLD-OPERATING A-TYPE K+ CURRENT IN dorsal root ganglion (DRG) NEURONS We conducted whole-cell patch-clamp measurements to ask whether the electrophysiological properties of the IA in smallmedium diameter nociceptive DRG neurons (∼30 μm, ∼45 pF) are consistent with the expression of Kv4 channels
This study is a comprehensive investigation of the contribution of Kv4 channels to the subthreshold-operating IA in DRG neurons
Summary
Voltage-gated potassium (Kv) channels are quintessential regulators of electrical excitability in the nervous system. Within the superfamily of Shaker-related Kv channels, four sub-families (Kv1, Kv2, Kv3, and Kv4) are present in the nervous system of diverse organisms in the animal kingdom (Gutman et al, 2003; Salkoff et al, 1992). Chien et al (2007) employed quantitative immunohistochemistry in a neuropathic pain model to show an inverse link between mechanical hypersensitivity and the expressions of Kv3.4 and Kv4.3 in lumbar nociceptive DRG neurons from adult rats. In light of this evidence, it is reasonable to assume that Kv4 channels may underlie IA in nociceptive DRG neurons. Testing this hypothesis more directly and systematically is a prerequisite toward understanding the mechanisms underlying nociception and pain plasticity
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