Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are integral membrane proteins that serve as nonselective voltage-gated cation channels in the plasma membranes of heart and brain cells.[1] HCN channels are sometimes referred to as pacemaker channels because they help to generate rhythmic activity within groups of heart and brain cells. HCN channels are activated by membrane hyperpolarization, are permeable to Na + and K +, and are constitutively open at voltages near the resting membrane potential.[2] HCN channels are encoded by four genes (HCN1, 2, 3, 4) and are widely expressed throughout the heart and the central nervous system.[3][4]
The current through HCN channels, designated If or Ih, plays a key role in the control of cardiac and neuronal rhythmicity and is called the pacemaker current or "funny" current. Expression of single isoforms in heterologous systems such as human embryonic kidney (HEK) cells, Chinese hamster ovary (CHO) cells and Xenopus oocytes yield homotetrameric channels able to generate ion currents with properties similar to those of the native If/Ih current, but with quantitative differences in the voltage-dependence, activation/deactivation kinetics and sensitivity to the nucleotide cyclic AMP (cAMP): HCN1 channels have a more positive threshold for activation, faster activation kinetics, and a lower sensitivity to cAMP, while HCN4 channels are slowly gating and strongly sensitive to cAMP. HCN2 and HCN3 have intermediate properties.[5][6][7]
- ^ Luthi A, McCormick DA. 1998. Neuron. H-current: properties of a neuronal and network pacemaker. Vol. 21. pp 9-12.
- ^ Benarroch EE. HCN channels: function and clinical implications. Neurology. 2013 Jan 15;80(3):304-10. doi: 10.1212/WNL.0b013e31827dec42. PMID 23319474.
- ^ Kaupp UB, Seifert R. Molecular diversity of pacemaker ion channels (2001) Annu Rev Physiol. 63:235-57. Review.
- ^ Notomi, T; Shigemoto, R (2004). "Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain". J Comp Neurol. 471 (3): 241–276. doi:10.1002/cne.11039. PMID 14991560. S2CID 12236560.
- ^ Wahl-Schott, C; Biel, M (Feb 2009). "HCN channels: structure, cellular regulation and physiological function". Cell Mol Life Sci. 66 (3): 470–94. doi:10.1007/s00018-008-8525-0. PMC 11131499. PMID 18953682. S2CID 12774911.
- ^ Baruscotti, M.; Bucchi, A.; DiFrancesco, D. (2005). "Physiology and pharmacology of the cardiac pacemaker ("funny") current". Pharmacology & Therapeutics. 107 (1): 59–79. doi:10.1016/j.pharmthera.2005.01.005. PMID 15963351.
- ^ Santoro, B; Tibbs, GR (1999). "The HCN gene family: molecular basis of the hyperpolarization-activated pacemaker channels". Ann N Y Acad Sci. 868 (1): 741–64. Bibcode:1999NYASA.868..741S. doi:10.1111/j.1749-6632.1999.tb11353.x. PMID 10414361. S2CID 38066720.
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