Expression of the pacemaker channel HCN4 in excitatory interneurons in the dorsal horn of the murine spinal cord
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RESEARCH
Open Access
Expression of the pacemaker channel HCN4 in excitatory interneurons in the dorsal horn of the murine spinal cord Taku Nakagawa1,2, Toshiharu Yasaka3, Noriyuki Nakashima1, Mitsue Takeya1, Kensuke Oshita1,4, Makoto Tsuda5, Ken Yamaura2 and Makoto Takano1*
Abstract In the central nervous system, hyperpolarization-activated, cyclic nucleotide-gated (HCN1–4) channels have been implicated in neuronal excitability and synaptic transmission. It has been reported that HCN channels are expressed in the spinal cord, but knowledge about their physiological roles, as well as their distribution profiles, appear to be limited. We generated a transgenic mouse in which the expression of HCN4 can be reversibly knocked down using a genetic tetracycline-dependent switch and conducted genetically validated immunohistochemistry for HCN4. We found that the somata of HCN4-immunoreactive (IR) cells were largely restricted to the ventral part of the inner lamina II and lamina III. Many of these cells were either parvalbumin- or protein kinase Cγ (PKCγ)-IR. By using two different mouse strains in which reporters are expressed only in inhibitory neurons, we determined that the vast majority of HCN4-IR cells were excitatory neurons. Mechanical and thermal noxious stimulation did not induce c-Fos expression in HCN4-IR cells. PKCγ-neurons in this area are known to play a pivotal role in the polysynaptic pathway between tactile afferents and nociceptive projection cells that contributes to tactile allodynia. Therefore, pharmacological and/or genetic manipulations of HCN4expressing neurons may provide a novel therapeutic strategy for the pain relief of tactile allodynia. Keywords: Hyperpolarization-activated cyclic nucleotide-gated channels, Spinal cord, Immunohistochemistry, Protein kinase Cγ, Parvalbumin, Glutamate decarboxylase 67, Vesicular GABA transporter, Vesicular glutamate transport protein 2, Tactile allodynia
Introduction Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels are expressed in both the peripheral nervous system (PNS) and central nervous system (CNS), and these ion channels generate the hyperpolarization-activated, nonselective cation current (Ih). The HCN channel family comprises four subtypes (HCN1–4) that form heteromultimers. Among those, HCN1 and HCN4 possess the fastest and slowest activation kinetics upon hyperpolarization, respectively. The voltage-dependence of activation of HCN2 and * Correspondence: [email protected] 1 Department of Physiology, Kurume University School of Medicine, 67 Asahi-Machi, Kurume 830-0011, Japan Full list of author information is available at the end of the article
HCN4 is highly sensitive to cyclic adenosine monophosphate (cAMP), whereas that of HCN1 and HCN3 is almost insensitive to cAMP [1]. In the PNS, HCN1 and HCN2 are the major isoforms expressed in the dorsal root ganglion (DRG). HCN4, a well-known pacemaker channel in the sinoatrial node, is expressed in a minor population of trigeminal ganglion and DRG neurons [2]. Most notably, H
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