HCN channels: Function and clinical implications

From the Department of Neurology, Mayo Clinic, Rochester, MN.
Neurology (Impact Factor: 8.29). 01/2013; 80(3):304-10. DOI: 10.1212/WNL.0b013e31827dec42
Source: PubMed


The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels belong to the superfamily of pore-loop cation channels. In mammals, the HCN channel family comprises 4 members (HCN1-4) that are expressed in heart and nervous system. HCN channels are activated by membrane hyperpolarization, are permeable to Na(+) and K(+), and are constitutively open at voltages near the resting membrane potential. In many cases, activation is facilitated by direct interaction with cyclic nucleotides, particularly cyclic adenosine monophosphate (cAMP). The cation current through HCN channels is known as I(h); opening of HCN channels elicits membrane depolarization toward threshold for action potential generation, and reduces membrane resistance and thus the magnitude of excitatory and inhibitory postsynaptic potentials. HCN channels have a major role in controlling neuronal excitability, dendritic integration of synaptic potentials, synaptic transmission, and rhythmic oscillatory activity in individual neurons and neuronal networks. These channels participate in mechanisms of synaptic plasticity and memory, thalamocortical rhythms, and somatic sensation. Experimental evidence indicates that HCN channels may also contribute to mechanisms of epilepsy and pain. The physiologic functions of HCN channels and their implications for neurologic disorders have been recently reviewed.(1-10).

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    • "Thus, ion channels or currents that operate in the sub threshold range of action potential firing are of particular interest. Examples of such currents are slow K + , persistent Na + , and HCN currents (Ih) (Benarroch, 2013; Maljevic et al., 2010). We show here that patients with cramp and fasciculation , whose routine electrophysiological studies provided evidence of axonal hyperexcitability (e.g., after-discharges, fasciculation potentials, multiplets) demonstrated distinctive axonal excitability features. "
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    ABSTRACT: Objective Cramp-fasciculation syndrome (CFS) is a heterogeneous condition with multiple underlying causes. Although dysfunction of slow K+ channels has been reported in patients with CFS, testing all potential candidates for this problem using conventional in vitro functional analysis would be prohibitively cost- and labor-intensive. However, relatively economical and non-invasive nerve-excitability testing can identify ion channel dysfunction in vivo when combined with numerical modeling. Methods Patients with CFS underwent nerve conduction study, needle electromyography, and nerve excitability testing. Mathematical modeling of axonal properties was applied to identify the pathophysiology. Results Four patients had distinct electrophysiological findings (i.e., fasciculation potentials, doublet/multiplet motor unit potentials, and sustained F responses); excitability testing showed the following abnormalities: reduction of accommodation during prolonged depolarization, lack of late sub excitability after a supramaximal stimulation, and reduction of the strength-duration time constant. Mathematical modeling showed a loss of voltage-dependence of a slow K+ current. None of these patients had a mutation in the KCNQ2, 3, or 5 genes. Conclusions This study showed that patients with CFS might have abnormal kinetics in a slow K+ current. Significance Nerve-excitability testing may aid the decision to start therapeutic intervention such as administration of slow K+ channel openers.
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