Role of the hyperpolarization‐activated current I_h in somatosensory neurons

Abstract

The hyperpolarization-activated current (I h ) is an inward current activated by hyperpolarization from the resting potential and is an important modulator of action potential firing frequency in many excitable cells. Four hyperpolarization-activated, cyclic nucleotide-modulated subunits, HCN1-4, can form I h ion channels. In the present study we investigated the function of I h in primary somatosensory neurons. Neuronal firing in response to current injection was promoted by elevating intracellular cAMP levels and inhibited by blockers of I h , suggesting that I h plays a critical role in modulating firing frequency. The properties of I h in three size classes of sensory neurons were next investigated. In large neurons I h was fast activating and insensitive to elevations in cAMP, consistent with expression of HCN1. I h was ablated in most large neurons in HCN1 −/− mice. In small neurons a slower activating, cAMP-sensitive I h was observed, as expected for expression of HCN2 and/or HCN4. Consistent with this, I h in small neurons was unchanged in HCN1 −/− mice. In a neuropathic pain model HCN1 −/− mice exhibited substantially less cold allodynia than wild-type littermates, suggesting an important role for HCN1 in neuropathic pain. This work shows that I h is an important modulator of action potential generation in somatosensory neurons.

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

“…Cyclic nucleotide sensitivity applies in particular to HCN2 and HCN4 channels that are expressed in small sensory neurons, whereas HCN1 channels dominate in the larger-size neurons and are not facilitated by cyclic nucleotides but by low extracellular pH (443,507,675). In cultured rat DRG neurons, PGE 2 increased action potential frequency elicited by a current pulse and induced a depolarizing shift in the resting potential with both effects being antagonized by a specific I h blocker but remaining largely unaltered by a PKA inhibitor suggesting a role for HCN2 and HCN4 channels (506). A contribution of I h to various nociceptive manifestations of neuropathic pain and also mild heat injury has been established raising the possibility that HCN channels may have a significant role in actions of prostanglandins on peripheral nociceptive nerve terminals (97,174,445,506 , and Ca 2ϩ in small cultured DRG neurons of neonatal rats (106).…”

“…In cultured rat DRG neurons, PGE 2 increased action potential frequency elicited by a current pulse and induced a depolarizing shift in the resting potential with both effects being antagonized by a specific I h blocker but remaining largely unaltered by a PKA inhibitor suggesting a role for HCN2 and HCN4 channels (506). A contribution of I h to various nociceptive manifestations of neuropathic pain and also mild heat injury has been established raising the possibility that HCN channels may have a significant role in actions of prostanglandins on peripheral nociceptive nerve terminals (97,174,445,506 , and Ca 2ϩ in small cultured DRG neurons of neonatal rats (106). Sensitization manifested itself as a decrease in activation threshold and a leftward shift of the pressure-activity curve, and it was mediated by the cAMP-PKA pathway.…”

HCN1 Channels as Targets for Anesthetic and Nonanesthetic Propofol Analogs in the Amelioration of Mechanical and Thermal Hyperalgesia in a Mouse Model of Neuropathic Pain

“…These effects appear to be due, in part, to changes in hyperpolarization-activated, cyclic nucleotide-regulated channel (HCN) channel expression and function. First, in situ hybridization (Kouranova et al, 2008), immunohistochemical (Tu et al, 2004;Jiang et al, 2008;Kouranova et al, 2008), and electrophysiological (Mayer and Westbrook, 1983;Kouranova et al, 2008;Momin et al, 2008) data show that sensory neurons express HCN channels, and that injury causes altered HCN subunit trafficking (Chaplan et al, 2003;Jiang et al, 2008) and enhanced I H current amplitudes (Chaplan et al, 2003;Yao et al, 2003). Second, sensory cell hyperexcitability is inhibited by superfusion with N-ethyl-1,6-dihydro-1,2-dimethyl-6-(methylimino)-N-phenyl-4-pyrimidinamine hydrochloride (ZD7288) (Chaplan et al, 2003;Yao et al, 2003;Jiang et al, 2008), a selective pan-isoform inhibitor of HCN channels, and systemic, but not central, administration of ZD7288 alleviates mechanical allodynia (Chaplan et al, 2003;Lee et al, 2005).…”

Sensitisation of Nociceptors – What are Ion Channels Doing?

“…The hyperpolarisation-evoked current can be enhanced by cAMP and, to a lesser extent, by cGMP by direct binding to a C-terminal site, which causes a shift in channel activation to more positive membrane potentials [249]. Voltage-clamp studies in DRG neurones showed that large neurones expressed a fast, cAMP-insensitive I h in large neurones, and that this current was abolished by genetic deletion of HCN1, while in small neurones a slower, cAMP-sensitive current, consistent with expression of HCN2, was seen [250]. In small neurones the enhanced generation of action potentials caused by exposure to PGE 2 was found to be entirely attributable to the cAMP-sensitivity of I h , and other factors such as modulation of Na currents (see above) played at most a marginal role [250].…”