Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are integral membrane
proteins that serve as
nonselectivevoltage-gatedcationchannels 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 Xenopusoocytes 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]
Structure
Hyperpolarization-activated and cyclic nucleotide–gated (HCN) channels belong to the superfamily of
voltage-gated K+ (Kv) and
cyclic nucleotide–gated (CNG) channels. HCN channels are thought to consist of four either identical or non-identical subunits that are integrally embedded in the
cell membrane to create an ion-conducting pore.[8] Each subunit comprises six membrane-spanning (S1–6) domains which include a putative voltage sensor (S4) and a pore region between S5 and S6 carrying the GYG triplet signature of K+-permeable channels, and a
cyclic nucleotide-binding domain (CNBD) in the C-terminus. HCN isoforms are highly conserved in their core transmembrane regions and cyclic nucleotide binding domain (80–90% identical), but diverge in their amino- and carboxy-terminal cytoplasmic regions.[6]
HCN channels are regulated by both intracellular and extracellular molecules[clarification needed], but most importantly, by cyclic nucleotides (cAMP, cGMP, cCMP).[9][10][11] Binding of cyclic nucleotides lowers the threshold potential of HCN channels, thus activating them. cAMP is a primary agonist of HCN2 while cGMP and cCMP may also bind to it. All three, however, are potent agonists.[12]
Cardiac function
HCN4 is the main isoform expressed in the
sinoatrial node, but low levels of HCN1 and HCN2 have also been reported.
The current through HCN channels, called the
pacemaker current (If), plays a key role in the generation and modulation of
cardiac rhythmicity,[13] as they are responsible for the spontaneous depolarization in pacemaker action potentials in the heart. HCN4 isoforms are regulated by cCMP and cAMP and these molecules are agonists at If.[14][15]
Function in the nervous system
All four HCN subunits are expressed in the brain.[4] In addition to their proposed roles in pacemaking rhythmic or oscillatory activity, HCN channels may control the way that
neurons respond to synaptic input. Initial studies suggest roles for HCN channels in sour taste, coordinated motor behavior and aspects of learning and memory. Clinically, there is evidence that HCN channels play roles in
epilepsy and
neuropathic pain. HCN channels have been shown to be important for activity-dependent mechanisms for olfactory sensory neuron growth.[16]
HCN1 and 2 channels have been found in
dorsal root ganglia,
basal ganglia, and the
dendrites of neurons in the
hippocampus. It has been found that human cortical neurons have particularly high amount of HCN1 channel expression in all layers.[17] HCN channel trafficking along dendrites in the hippocampus of rats has shown that HCN channels are quickly shuttled to the surface in response to neural activity.[18] HCN channels have also been observed in the retrotrapezoid nucleus (RTN), a respiratory control center that responds to chemical signals such as CO2.[citation needed] When HCN is inhibited,
serotonin fails to stimulate chemoreceptors in the RTN. This illustrates a connection between HCN channels and
respiratory regulation.[19] Due to the complex nature of HCN channel regulation, as well as the complex interactions between multiple ion channels, HCN channels are fine-tuned to respond to certain thresholds and agonists. This complexity is believed to affect
neural plasticity.[18]
History
HCN channel was first identified in 1976 in the heart by Noma and Irisawa and characterized by Brown, Difrancesco and Weiss [20]
^Mishra, Poonam; Narayanan, Rishikesh (2015-01-01). "High-conductance states and A-type K+ channels are potential regulators of the conductance-current balance triggered by HCN channels". Journal of Neurophysiology. 113 (1): 23–43.
doi:
10.1152/jn.00601.2013.
ISSN0022-3077.
PMID25231614.