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
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).
Available from: Satoshi Kuwabara
- "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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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.
Patients with CFS underwent nerve conduction study, needle electromyography, and nerve excitability testing. Mathematical modeling of axonal properties was applied to identify the pathophysiology.
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.
This study showed that patients with CFS might have abnormal kinetics in a slow K+ current.
Nerve-excitability testing may aid the decision to start therapeutic intervention such as administration of slow K+ channel openers.
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The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning, and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs.
PDE4 is the largest of the 11 mammalian PDE families. This review covers the properties and functions of the PDE4 family, highlighting procognitive and memory-enhancing effects associated with their inactivation.
PAN-selective PDE4 inhibitors exert a number of memory- and cognition-enhancing effects and have neuroprotective and neuroregenerative properties in preclinical models. The major hurdle for their clinical application is to target inhibitors to specific PDE4 isoforms relevant to particular cognitive disorders to realize the therapeutic potential while avoiding side effects, in particular emesis and nausea. The PDE4 family comprises four genes, PDE4A-D, each expressed as multiple variants. Progress to date stems from characterization of rodent models with selective ablation of individual PDE4 subtypes, revealing that individual subtypes exert unique and non-redundant functions in the brain. Thus, targeting specific PDE4 subtypes, as well as splicing variants or conformational states, represents a promising strategy to separate the therapeutic benefits from the side effects of PAN-PDE4 inhibitors.
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ABSTRACT: The core challenge of pain management in neurocritical care is to keep the patient comfortable without masking or overlooking any neurological deterioration. Clearly in patients with a neurological problem there is a conflict of clinical judgement and adequate pain relief. Here we review the presentation, assessment, and development of pain in the clinical spectrum of patients with associated neurological problems seen in a general intensive care setting. Many conditions predispose to the development of chronic pain. There is evidence that swift and targeted pain management may improve the outcome. Importantly pain management is multidisciplinary. The available non-invasive, pharmacological, and invasive treatment strategies are discussed.
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