Correlation Engine 2.0
Clear Search sequence regions

  • activity (2)
  • cation (2)
  • cells (1)
  • cGMP (1)
  • cump (1)
  • cyclic (4)
  • HCN (3)
  • HCN2 (2)
  • HCN4 (2)
  • heart rate (1)
  • humans (1)
  • ion channels (8)
  • isoforms (2)
  • ligands (2)
  • models molecular (1)
  • nucleotides cyclic (5)
  • nucleotides cyclic (3)
  • partial (5)
  • Sizes of these terms reflect their relevance to your search.

    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.


    Bryan VanSchouwen, Giuseppe Melacini. Regulation of HCN Ion Channels by Non-canonical Cyclic Nucleotides. Handbook of experimental pharmacology. 2017;238:123-133

    Expand section icon Mesh Tags

    Expand section icon Substances

    PMID: 28181007

    View Full Text