HCN4 Membrane Protein Introduction

Introduction of HCN4

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4, which in human is encoded by HCN4 gene, is a multi-pass membrane protein that belongs to the hyperpolarization-activated cyclic nucleotide-gated potassium channels (HCN) family. It functions as a voltage-gated cation channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. HCN4 channel is primarily expressed in the pacemaker region of the mammalian heart.

Basic Information of HCN4
Protein Name	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
Gene Name	HCN4
Aliases	N/A
Organism	Homo sapiens (Human)
UniProt ID	Q9Y3Q4
Transmembrane Times	6
Length (aa)	1,203
Sequence	MDKLPPSMRKRLYSLPQQVGAKAWIMDEEEDAEEEGAGGRQDPSRRSIRLRPLPSPSPSAAAGGTESRSSALGAADSEGPARGAGKSSTNGDCRRFRGSLASLGSRGGGSGGTGSGSSHGHLHDSAEERRLIAEGDASPGEDRTPPGLAAEPERPGASAQPAASPPPPQQPPQPASASCEQPSVDTAIKVEGGAAAGDQILPEAEVRLGQAGFMQRQFGAMLQPGVNKFSLRMFGSQKAVEREQERVKSAGFWIIHPYSDFRFYWDLTMLLLMVGNLIIIPVGITFFKDENTTPWIVFNVVSDTFFLIDLVLNFRTGIVVEDNTEIILDPQRIKMKYLKSWFMVDFISSIPVDYIFLIVETRIDSEVYKTARALRIVRFTKILSLLRLLRLSRLIRYIHQWEEIFHMTYDLASAVVRIVNLIGMMLLLCHWDGCLQFLVPMLQDFPDDCWVSINNMVNNSWGKQYSYALFKAMSHMLCIGYGRQAPVGMSDVWLTMLSMIVGATCYAMFIGHATALIQSLDSSRRQYQEKYKQVEQYMSFHKLPPDTRQRIHDYYEHRYQGKMFDEESILGELSEPLREEIINFNCRKLVASMPLFANADPNFVTSMLTKLRFEVFQPGDYIIREGTIGKKMYFIQHGVVSVLTKGNKETKLADGSYFGEICLLTRGRRTASVRADTYCRLYSLSVDNFNEVLEEYPMMRRAFETVALDRLDRIGKKNSILLHKVQHDLNSGVFNYQENEIIQQIVQHDREMAHCAHRVQAAASATPTPTPVIWTPLIQAPLQAAAATTSVAIALTHHPRLPAAIFRPPPGSGLGNLGAGQTPRHLKRLQSLIPSALGSASPASSPSQVDTPSSSSFHIQQLAGFSAPAGLSPLLPSSSSSPPPGACGSPSAPTPSAGVAATTIAGFGHFHKALGGSLSSSDSPLLTPLQPGARSPQAAQPSPAPPGARGGLGLPEHFLPPPPSSRSPSSSPGQLGQPPGELSLGLATGPLSTPETPPRQPEPPSLVAGASGGASPVGFTPRGGLSPPGHSPGPPRTFPSAPPRASGSHGSLLLPPASSPPPPQVPQRRGTPPLTPGRLTQDLKLISASQPALPQDGAQTLRRASPHSSGESMAAFPLFPRAGGGSGGSGSSGGLGPPGRPYGAIPGQHVTLPRKTSSGSLPPPLSLFGARATSSGGPPLTAGPQREPGARPEPVRSKLPSNL

Function of HCN4 Membrane Protein

Hyperpolarization-activated cyclic nucleotide-gated channels are a unique group of voltage-gated ion channels in which the threshold voltage for the opening of the channel is regulated by the metabolic state of the cell (levels of cyclic nucleotides like cAMP). The channels open upon hyperpolarized membrane voltages (negative), generating a large current which is a mix of sodium and potassium ion fluxes. Primarily, HCN4 channels have been studied in adult hearts as pacemaker channels. But, recent studies have demonstrated their presence in human embryonic cells and implicated them in cardiac patterning. HCN4 channels show slow kinetics of activation and inactivation and contribute to the native pacemaker currents in heart (If) that regulate the rhythm of the heartbeat. They show an essential role for the cardiac pacemaking process. HCN4 channels may also responsible for the native pacemaker currents in neurons (Ih), and may mediate responses to sour stimuli. Mutations in HCN4 gene have shown to be linked to sick sinus syndrome 2, which is also known as atrial fibrillation with bradyarrhythmia or familial sinus bradycardia.

Fig.1 Structure of potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4.

Application of HCN4 Membrane Protein in Literature

Pai V.P., et al. HCN4 ion channel function is required for early events that regulate anatomical left-right patterning in a nodal and lefty asymmetric gene expression-independent manner. Biol Open. 2017, 6(10): 1445-1457. PubMed ID: 28818840

Data of this article identify a novel, developmental role for HCN4 channels in correct left-right patterning.
Kozasa Y., et al. HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of the sinoatrial node. J Physiol. 2018, 596(5): 809-825. PubMed ID: 29315578

This article reveals that HCN4 channels attenuate the vagal response of the SAN, and thus stabilize the spontaneous firing of the SAN.
Pitcairn E., et al. Coordinating heart morphogenesis: A novel role for hyperpolarization-activated cyclic nucleotide-gated (HCN) channels during cardiogenesis in Xenopus laevis. Commun Integr Biol. 2017, 10(3): e1309488. PubMed ID: 28702127

This article indicates that HCN4 serves to coordinate morphogenetic control factors that provide positional information during heart morphogenesis in Xenopus.
Verkerk A.O and Wilders R. Pacemaker Activity of the Human Sinoatrial Node: An Update on the Effects of Mutations in HCN4 on the Hyperpolarization-Activated Current. Int J Mol Sci. 2015, 16(2): 3071-3094. PubMed ID: 25642760

Findings of this article provide an updated review of the mutation-induced changes in the expression and kinetics of HCN4 channels.
Saito Y., et al. Enhancement of Spontaneous Activity by HCN4 Overexpression in Mouse Embryonic Stem Cell-Derived Cardiomyocytes - A Possible Biological Pacemaker. PLoS One. 2015, 10(9): e0138193. PubMed ID: 26384234

Authors of this article generate HCN4-overexpressing mESC-CMs expressing genes required for impulse conduction, showing rapid spontaneous beating, responding to an If inhibitor and beta-adrenergic receptor agonist.

HCN4 Preparation Options

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