Hyperpolarization‐activated, cyclic nucleotide‐gated cation channels: Roles in the differential electrophysiological properties of rat primary afferent neurons

Abstract

The large, medium-sized, and small neurons of the dorsal root ganglion (DRG) have different functions in the processing of various senses. Hyperpolarization-activated, cyclic nucleotide-gated channels (HCN) contribute greatly to neuronal excitability. In the present study, which used whole-cell patch clamp techniques and immunohistochemical staining methods, the electrophysiological properties of DRG neurons were systematically compared, and the roles of HCN-1, -2, and -4 were examined. The main results were as follows. 1) The large neurons had significantly higher V0.5 values (membrane potential at which the HCN channels were half-activated) and shorter time constants (tau) than small or medium-sized DRG neurons. However, large DRG neurons had higher Ih density (HCN neuron current). 2) HCN-1 was found predominantly, but not exclusively, in large and medium-sized DRG neurons; HCN-2 was found in all DRG neurons; and HCN-4 was poorly visualized in all DRG neurons. HCN-1 and HCN-2 were colocalized in large and medium-sized neurons with immunostaining of adjacent sections. In the dorsal horn of the spinal cord, HCN-1, HCN-2, and HCN-4 were all expressed in laminae I-IV, although HCN-1 was not detectable in lamina II. 3) Blockade of Ih current in DRG neurons caused a significant decrease in V0.5, resting membrane potential, and repetitive firing number of action potential and a significant increase in time of rising phase of action potential. These results suggest that the different HCN channels in the three types of DRG neurons might contribute to their differential electrophysiological properties.

Hyperpolarization-activated current (Ih) contributes to excitability of primary sensory neurons in rats

“…This may result from preferential activation of I h during the AHP (Maccaferri and McBain, 1996). The absence of this effect in Aα/β neurons may be a consequence of the different I h kinetics in these DRG neuronal populations (Tu et al, 2004).…”

“…Few observations are available to discern the role of I h in sensory neurons. Block of I h with the nonspecific agent clonidine resulted in reduced repetitive firing in partially digested DRG neurons (Yagi and Sumino, 1998), as did the specific agent ZD7288 in a small number of dissociated DRG neurons (Tu et al, 2004). However, measurement of I h is influenced by both temperature and cytoplasmic dialysis (Cuevas et al, 1997), and dissociation produces an injury-like effect on neuronal excitability (Zheng et al, 2007).…”

“…The hyperpolarization-activated, cyclic nucleotide-gated current, also termed the anomalous rectifier current or H-current (I h ), is expressed in sensory neurons, particularly large neurons with myelinated axons (Scroggs et al, 1994;Tu et al, 2004;Vasilyev et al, 2007). This current is activated by membrane potentials negative to −60mV (Yao et al, 2003) and does not inactivate, and therefore is in a conducting state at resting membrane potentials (RMPs) typical of sensory neurons.…”

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).…”

Comparison of effects of PKA catalytic subunit on Ih and calcium channel currents in rat dorsal root ganglion cells

“…C-neurons that extended unmyelinated axons with a slow conduction velocity were found among neurons with a smaller diameter, and A-neurons that extended myelinated axons with a fast conduction velocity were found among neurons with a large diameter (8,9). DRG neurons in the different groups were reported to have hyperpolarization-activated currents (I h ) with different electrophysiological properties (26,30). Since the electrophysiological properties of I h were reported to differ depending on the subtype of HCN channels, it was important to know which subtypes were expressed in focused neurons.…”