Hyperpolarization-activated cyclic-nucleotide-gated channels potentially modulate axonal excitability at different thresholds

Abstract

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels mediate differences in sensory and motor axonal excitability at different thresholds in animal models. Importantly, HCN channels are responsible for voltage-gated inward rectifying (I_h) currents activated during hyperpolarization. The I_h currents exert a crucial role in determining the resting membrane potential and have been implicated in a variety of neurological disorders, including neuropathic pain. In humans, differences in biophysical properties of motor and sensory axons at different thresholds remain to be elucidated and could provide crucial pathophysiological insights in peripheral neurological diseases. Consequently, the aim of this study was to characterize sensory and motor axonal function at different threshold. Median nerve motor and sensory axonal excitability studies were undertaken in 15 healthy subjects (45 studies in total). Tracking targets were set to 20, 40, and 60% of maximum for sensory and motor axons. Hyperpolarizing threshold electrotonus (TEh) at 90-100 ms was significantly increased in lower threshold sensory axons times (F = 11.195, P < 0.001). In motor axons, the hyperpolarizing current/threshold (I/V) gradient was significantly increased in lower threshold axons (F = 3.191, P < 0.05). The minimum I/V gradient was increased in lower threshold motor and sensory axons. In conclusion, variation in the kinetics of HCN isoforms could account for the findings in motor and sensory axons. Importantly, assessing the function of HCN channels in sensory and motor axons of different thresholds may provide insights into the pathophysiological processes underlying peripheral neurological diseases in humans, particularly focusing on the role of HCN channels with the potential of identifying novel treatment targets.NEW & NOTEWORTHY Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, which underlie inward rectifying currents (I_h), appear to mediate differences in sensory and motor axonal properties. Inward rectifying currents are increased in lower threshold motor and sensory axons, although different HCN channel isoforms appear to underlie these changes. While faster activating HCN channels seem to underlie I_h changes in sensory axons, slower activating HCN isoforms appear to be mediating the differences in I_h conductances in motor axons of different thresholds. The differences in HCN gating properties could explain the predilection for dysfunction of sensory and motor axons in specific neurological diseases.

Keywords: hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels; sensory axon; threshold.

Fig. 1.

A: there was a significant increase in the hyperpolarizing threshold electrotonus (TEh) at 90–100 ms and hyperpolarizing TEh slope (101–140 ms) in sensory axons at the 60% tracking target. In addition, the depolarizing TE peak and depolarization at 10–20 ms (TEd 10–20 ms) were significantly reduced in sensory axons at the higher tracking target (60%). This finding is likely to be accounted for by the presence of the depolarizing notch (arrow). B: the hyperpolarizing threshold electrotonus at 90–100 ms [TEh (90–100 ms)] was significantly increased with tracking target set to 60% of maximum. C: there were no significant differences in the threshold electrotonus in motor axons between the tracking targets. ***P < 0.001; NS, not significant.

Fig. 2.

A and B: the hyperpolarizing current threshold (I/V) slope, which reflects the properties of inward axonal rectifying currents, was significantly increased in motor axons with tracking target set to 20 and 40% of maximum response but was similar in the sensory axons across the three tracking target levels.

Fig. 3.

The recovery cycle of axonal excitability was similar in sensory (A) and motor axons (B) across the three tracking target levels.