Inward rectifying channels as new targets for treatment

Abstract

It is now well known that axonal excitability properties are not identical in different human nerves. All human myelinated axons probably have similar resting membrane potential and outward rectifying potassium conductances, and share a common microstructure of nodes of Ranvier. However, there are significant differences in excitability and accommodative properties between sensory and motor axons (Bostock et al. 1994), between axons in the upper and lower limb nerves, between distal and proximal axons, and even between motor axons in the same nerve innervating different muscles (Bae et al. 2009). This is presumably because axonal properties are adapted to the pattern of impulse traffic normally carried by the axons. For example, sensory axons have more prominent persistent sodium channels that are open at rest (Bostock & Rothwell, 1997), and this explains why axonal firing threshold to electrical stimulation is always lower in sensory than in motor axons. Furthermore, inward rectifying conductances, usually driven in response to prolonged membrane hyperpolarization, appear to be expressed more on sensory axons than motor axons. Overall, excitability of sensory axons is physiologically higher than that of motor axons, leading to more ready development of ectopic activity (paraesthesiae or pain), and possibly to less susceptibility to nerve conduction block. Thus, the properties of different axons are not identical and their responses to injury or disease may therefore differ. In human motor axons, similar correlations of excitability properties with different responses to disease have been proposed. Fasciculation is a characteristic feature of amyotrophic lateral sclerosis (ALS). The ectopic firing of motor units usually arises from the motor nerve terminals, indicating a widespread abnormality in axonal excitability properties. So far, two kinds of axonal ion channel abnormalities have been found in ALS; increased persistent sodium currents, and reduced potassium currents, both increasing axonal excitability and responsible for generation of fasciculations (Kanai et al. 2006). The first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles are innervated by the same ulnar nerve, but studies have shown that the former is much more severely affected in ALS. This peculiar pattern of dissociated atrophy of the intrinsic hand muscles has been termed the ‘split hand’. Nodal persistent sodium conductances are much more prominent in FDI axons than in ADM axons, and the physiologically higher excitability could promote motor neuronal death in ALS (Bae et al. 2009). Previous excitability studies have focused on altered persistent sodium channels as major determinants of axonal excitability in motor neuron diseases and peripheral neuropathies. In a recent issue of The Journal of Physiology, the study by Trevillion et al. (2010) investigated the excitability and accommodative properties of low-threshold human median motor axons in healthy subjects. The authors, as well as many investigators, originally hypothesized that greater expression of persistent sodium channels on low-threshold axons could be the reason for the low threshold to electrical stimulation. However, their findings did not support a difference in persistent sodium conductance, and instead they nicely demonstrated greater activity of the hyperpolarization-activated inwardly rectifying current as the basis for low threshold to electrical recruitment. The results are somewhat surprising, but the provided data appear very convincing. The authors suggest that the inward rectifying channels expressed on human motor axons may be active at rest and contribute to resting membrane potential. The observation is novel, and could provide new insight into the pathophysiology in a variety of neurological disorders. Altered inward rectifying channels should be taken into consideration in the future researches on ALS and neuropathic pain. In ALS, in addition to altered sodium and potassium channels, it should be investigated whether inward rectification channels contribute to increased axonal excitability and thereby enhance motor neuronal death. Regarding neuropathic pain, as the authors cited, an experimental study using a nerve ligation model in the rat has shown that hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels play an important role in both pain and spontaneous neuronal discharge originating in the damaged dorsal root ganglion (Chaplan et al. 2003). HCN channels are abundantly expressed in rat primary afferent somata. Nerve injury markedly increases the currents in large-diameter dorsal root ganglion neurons and in spontaneous action potentials. Pharmacological blockade of HCN activity reverses abnormal hypersensitivity to light touch and decreases the firing frequency of ectopic discharges. Previous excitability studies rarely focused on HCN inward rectifying channels, the function of which can be reliably estimated by current–threshold relationships with computerized threshold tracking, as shown in the study by Trevillion et al. (2010). This relevant study raises the possibility that hyperpolarization-activated inward rectifying channels are active at rest, and directly affect membrane potential and thereby, axonal excitability. In future studies, HCN channels should be recognized as new targets for drug discovery in a variety of neurological disorders characterized by axonal hyperexcitability.