Regulation of HCN Ion Channels by Non-canonical Cyclic Nucleotides.
The hyperpolarization-activated cyclic-nucleotide-modulated (HCN) proteins are cAMP-regulated ion channels that play a key role in nerve impulse transmission and heart rate modulation in neuronal and cardiac cells, respectively. Although they are regulated primarily by cAMP, other cyclic nucleotides such as cGMP, cCMP, and cUMP serve as partial agonists for the HCN2 and HCN4 isoforms. By competing with cAMP for binding, these non-canonical ligands alter ion channel gating, and in turn, modulate the cAMP-dependent activation profiles. The partial activation of non-canonical cyclic nucleotides can be rationalized by either a partial reversal of a two-state inactive/active conformational equilibrium, or by sampling of a third conformational state with partial activity. Furthermore, different mechanisms and degrees of activation have been observed upon binding of non-canonical cyclic nucleotides to HCN2 versus HCN4, suggesting that these ligands control HCN ion channels in an isoform-specific manner. While more work remains to be done to achieve a complete understanding of ion channel modulation by non-canonical cyclic nucleotides, it is already clear that such knowledge will ultimately prove invaluable in achieving a more complete understanding of ion channel signaling in vivo, as well as in the development of therapeutics designed to selectively modulate ion channel gating.
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, ON, Canada, L8S 4M1.
Bryan
B
VanSchouwen
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, ON, Canada, L8S 4M1. melacin@mcmaster.ca.|Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, Canada, L8S 4M1. melacin@mcmaster.ca.
Giuseppe
G
Melacini
D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D054333:Drug Partial Agonism; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D015640:Ion Channel Gating; D008958:Models, Molecular; D009712:Nucleotides, Cyclic / Q000378:metabolism* / Q000494:pharmacology; D011487:Protein Conformation; D015290:Second Messenger Systems / Q000187:drug effects; D013329:Structure-Activity Relationship
D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009712:Nucleotides, Cyclic
Allostery; Binding domain; Canonical; Conformational equilibrium; Cyclic nucleotide; HCN; HCN2; HCN4; Ion channel; Isoform selectivity; Modulation; Non-canonical; Partial activation; cAMP; cCMP; cGMP; cUMP