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

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 (Ih) currents activated during hyperpolarization. The Ih 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 characterise sensory and motor axonal function at different threshold. Median nerve motor and sensory axonal excitability studies were undertaken in 15 health 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 (F=11.195, P<0.001). In motor axons, the hyperpolarizing 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.

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