Neurophysiology of HCN channels: from cellular functions to multiple regulations

Prog Neurobiol. 2014 Jan;112:1-23. doi: 10.1016/j.pneurobio.2013.10.001. Epub 2013 Oct 29.


Hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels are encoded by HCN1-4 gene family and have four subtypes. These channels are activated upon hyperpolarization of membrane potential and conduct an inward, excitatory current Ih in the nervous system. Ih acts as pacemaker current to initiate rhythmic firing, dampen dendritic excitability and regulate presynaptic neurotransmitter release. This review summarizes recent insights into the cellular functions of Ih and associated behavior such as learning and memory, sleep and arousal. HCN channels are excellent targets of various cellular signals to finely regulate neuronal responses to external stimuli. Numerous mechanisms, including transcriptional control, trafficking, as well as channel assembly and modification, underlie HCN channel regulation. In the next section, we discuss how the intracellular signals, especially recent findings concerning protein kinases and interacting proteins such as cGKII, Ca(2+)/CaMKII and TRIP8b, regulate function and expression of HCN channels, and subsequently provide an overview of the effects of neurotransmitters on HCN channels and their corresponding intracellular mechanisms. We also discuss the dysregulation of HCN channels in pathological conditions. Finally, insight into future directions in this exciting area of ion channel research is provided.

Keywords: 3′-5′-cyclic adenosine monophosphate; 5-HT; 5-HT(1) receptors; 5-HT(1)Rs; 5-hydroxytryptamine; AC; AMPA; AT1Rs; ATP; Ang II; Ang II type 1 receptors; CNBD; CNS; CST; Ca(2+)/CaMKII; D(1)Rs; DA; EC; EEG; EPSPs; Extracellular molecules; GABA; GC; GPe; HCN channel trafficking; HCN channels; Hyperpolarization-activated cyclic nucleotide-gated; I(T); I(h); IGL; LTD; LTP; Long-term depression; N-methyl D-aspartate; NE; NMDA; NO; NT; Nitric oxide; OXR(1/2); PACAP; PCs; PFC; PIP(2); PKC; PL; PLC; PSCs; Protein kinases; Purkinje cells; RMP; S-SCAM; SST; STN; TRIP8b; VIP; VTA; WM; adenosine triphosphate; adenylate cyclase; angiotensin II; cAMP; calcium/calmodulin-dependent protein kinase II; central nervous system; cortistatin; cyclic nucleotide-binding domain; dopamine; dopamine D(1) receptors; electroencephalography; entorhinal cortex; excitatory postsynaptic potentials; external of the globus pallidus; gamma-aminobutyric acid; hyperpolarization-activated current; intergeniculate leaflet; long-term depression; long-term potentiation; low-threshold Ca(2+) currents; mGluRs; metabotropic glutamate receptors; mouse prelimbic cortex; neurotensin; norepinephrine; orexin receptor type 1/type 2; p38-MAPK; p38-mitogen activated protein kinase; phosphatidylinositol 4,5-bisphosphate; phospholipase C; pituitary adenylate cyclase-activating polypeptide; postsynaptic currents; prefrontal cortex; protein kinase C; resting membrane potential; soluble guanylyl cyclase; somatostatin; subthalamic nucleus; synaptic scaffolding molecule; tetratricopeptide repeat-containing Rab8b-interacting protein; vasoactive intestinal polypeptide; ventral tegmental area; working memory; α(2)-ARs; α(2)-adrenoceptors; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Biological Clocks / physiology*
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / chemistry*
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / physiology*
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / ultrastructure
  • Ion Channel Gating / physiology*
  • Membrane Potentials / physiology*
  • Models, Neurological
  • Neurons / physiology*
  • Synaptic Transmission / physiology*


  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels