Cyclic nucleotide-gated (CNG) channels are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems.

CNG channels are voltage-independent cation channels formed as tetramers. Each subunit has 6TM, with the pore-forming domain between TM5 and TM6. CNG channels were first found in rod photoreceptors [9,12], where light signals through rhodopsin and transducin to stimulate phosphodiesterase and reduce intracellular cyclic GMP level. This results in a closure of CNG channels and a reduced ‘dark current’. Similar channels were found in the cilia of olfactory neurons [17] and the pineal gland [8]. The cyclic nucleotides bind to a domain in the C terminus of the subunit protein: other channels directly binding cyclic nucleotides include HCN, eag and certain plant potassium channels.

Hyperpolarisation-activated, cyclic nucleotide-gated (HCN)
The hyperpolarisation-activated, cyclic nucleotide-gated (HCN) channels are cation channels that are activated by hyperpolarisation at voltages negative to ~-50 mV. The cyclic nucleotides cyclic AMP and cyclic GMP directly bind to the cyclic nucleotide-binding domain of HCN channels and shift their activation curves to more positive voltages, thereby enhancing channel activity. HCN channels underlie pacemaker currents found in many excitable cells including cardiac cells and neurons [6,18]. In native cells, these currents have a variety of names, such as I_h, I_q and I_f. The four known HCN channels have six transmembrane domains and form tetramers. It is believed that the channels can form heteromers with each other, as has been shown for HCN1 and HCN4 [1]. High resolution structural studies of CNG and HCN channels has provided insight into the the gating processes of these channels [14-16]. A standardised nomenclature for CNG and HCN channels has been proposed by the NC-IUPHAR subcommittee on voltage-gated ion channels [11].

CNGA1, CNGA2 and CNGA3 express functional channels as homomers. Three additional subunits CNGA4 (Q8IV77), CNGB1 (Q14028) and CNGB3 (Q9NQW8) do not, and are referred to as auxiliary subunits. The subunit composition of the native channels is believed to be as follows. Rod: CNGA1₃/CNGB1a; Cone: CNGA3₂/CNGB3₂ [7]; Olfactory neurons: CNGA2₂/CNGA4/CNGB1b [19,24-27].

Hyperpolarisation-activated, cyclic nucleotide-gated (HCN)
HCN channels are permeable to both Na⁺ and K⁺ ions, with a Na⁺/K⁺ permeability ratio of about 0.2. Functionally, they differ from each other in terms of time constant of activation with HCN1 the fastest, HCN4 the slowest and HCN2 and HCN3 intermediate. The compounds ZD7288 [2] and ivabradine [3] have proven useful in identifying and studying functional HCN channels in native cells. Zatebradine and cilobradine are also useful blocking agents.

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Subcommittee members: Martin Biel (Chairperson) Ludwig-Maximilians-Universität Lehrstuhl Pharmakologie für Naturwissenschaften Zentrum für Pharmaforschung Department Pharmazie München Germany Elvir Becirovic Ludwig-Maximilians-Universität Lehrstuhl Pharmakologie für Naturwissenschaften Zentrum für Pharmaforschung Department Pharmazie München Germany Verena Hammelmann Ludwig-Maximilians-Universität Lehrstuhl Pharmakologie für Naturwissenschaften Zentrum für Pharmaforschung Department Pharmazie München Germany

Other contributors: Stefanie Fenske Ludwig-Maximilians-Universität Lehrstuhl Pharmakologie für Naturwissenschaften Zentrum für Pharmaforschung Department Pharmazie München Germany Franz Hofmann Institut für Pharmakologie und Toxikologie Technische Universität München München Germany U. Benjamin Kaupp Forschungszentrum Jülich Institut für Biologische Informationsverarbeitung Jülich Germany