HCN2 Membrane Protein Introduction

Introduction of HCN2

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2, also known as brain cyclic nucleotide-gated channel 2 or BCNG-2, is a membrane protein that in human is encoded by HCN2 gene. This channel protein belongs to the family of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, and consists of six transmembrane domains (S1-S6), four subunits form a functional channel, homotetramers, and heterotetramers. HCN2 channel is expressed throughout the brain and heart and is quite sensitive to the intracellular cAMP concentration.

Basic Information of HCN2
Protein Name	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2
Gene Name	HCN2
Aliases	Brain cyclic nucleotide-gated channel 2, BCNG-2
Organism	Homo sapiens (Human)
UniProt ID	Q9UL51
Transmembrane Times	6
Length (aa)	889
Sequence	MDARGGGGRPGESPGATPAPGPPPPPPPAPPQQQPPPPPPPAPPPGPGPAPPQHPPRAEALPPEAADEGGPRGRLRSRDSSCGRPGTPGAASTAKGSPNGECGRGEPQCSPAGPEGPARGPKVSFSCRGAASGPAPGPGPAEEAGSEEAGPAGEPRGSQASFMQRQFGALLQPGVNKFSLRMFGSQKAVEREQERVKSAGAWIIHPYSDFRFYWDFTMLLFMVGNLIIIPVGITFFKDETTAPWIVFNVVSDTFFLMDLVLNFRTGIVIEDNTEIILDPEKIKKKYLRTWFVVDFVSSIPVDYIFLIVEKGIDSEVYKTARALRIVRFTKILSLLRLLRLSRLIRYIHQWEEIFHMTYDLASAVMRICNLISMMLLLCHWDGCLQFLVPMLQDFPRNCWVSINGMVNHSWSELYSFALFKAMSHMLCIGYGRQAPESMTDIWLTMLSMIVGATCYAMFIGHATALIQSLDSSRRQYQEKYKQVEQYMSFHKLPADFRQKIHDYYEHRYQGKMFDEDSILGELNGPLREEIVNFNCRKLVASMPLFANADPNFVTAMLTKLKFEVFQPGDYIIREGTIGKKMYFIQHGVVSVLTKGNKEMKLSDGSYFGEICLLTRGRRTASVRADTYCRLYSLSVDNFNEVLEEYPMMRRAFETVAIDRLDRIGKKNSILLHKVQHDLNSGVFNNQENAIIQEIVKYDREMVQQAELGQRVGLFPPPPPPPQVTSAIATLQQAAAMSFCPQVARPLVGPLALGSPRLVRRPPPGPAPAAASPGPPPPASPPGAPASPRAPRTSPYGGLPAAPLAGPALPARRLSRASRPLSASQPSLPHGAPGPAASTRPASSSTPRLGPTPAARAAAPSPDRRDSASPGAAGGLDPQDSARSRLSSNL

Function of HCN2 Membrane Protein

Hyperpolarization-activated cyclic nucleotide-gated channels are a kind of voltage-gated channels, and they open upon hyperpolarization of the membrane in contrast to most other voltage-gated channels. HCN2 channel is identified as a hyperpolarization-activated cation channel involved in the generation of native pacemaker activity in the heart and brain and shows weak selectivity for potassium over sodium ions. HCN2 channels are activated by cAMP which influences their gating behavior, and also by cGMP at 10-100 times higher concentrations. The channel activity is regulated by intracellular chloride ions and pH; acidic pH shifts the activation to more negative voltages. cAMP binding results in a conformation change that leads to the assembly of an active tetramer and channel opening. HCN2 channels are involved in the generation of native pacemaker currents in heart (If) and in neurons (Ih). It can also transport ammonium in the distal nephron. Recently, the HCN2 channels have shown to be associated with chronic pain and are regarded as potential targets for neuropathic episodes of pain.

Fig.1 Structure of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2.

Application of HCN2 Membrane Protein in Literature

Pai V.P., et al. HCN2 Rescues brain defects by enforcing endogenous voltage pre-patterns. Nat Commun. 2018, 9: 998. PubMed ID: 29519998

Authors in this article describe a biophysical mechanism of developmental brain damage and its functional rescue by predicting that exogenous HCN2 ion channels would restore the endogenous bioelectric pre-patterns necessary for brain patterning.
Zhong P., et al. HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress. Inflammopharmacology. 2018, 7: e32420. PubMed ID: 29256865

This article reveals a crucial role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related behaviors.
Tsantoulas C., et al. Hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy. Sci Transl Med. 2017, 9(409):eaam6072. PubMed ID: 28954930

Findings of this article suggest that HCN2 may be an analgesic target in the treatment of painful diabetic neuropathy.
Boink G.J., et al. The Ca2+-stimulated adenylyl cyclase AC1 generates efficient biological pacing as single gene therapy and in combination with HCN2. Circulation. 2012, 126(5): 528-536. PubMed ID: 22753192

This article shows that AC1 or HCN2/AC1 overexpression in left bundle branches provides highly efficient biological pacing and greater sensitivity to autonomic modulation than HCN2 alone.
Bhatt B., et al. The cGMP-Dependent Protein Kinase II Is an Inhibitory Modulator of the Hyperpolarization-Activated HCN2 Channel. PLoS One. 2011, 6(2):e17078. PubMed ID: 21347269

The results of this article indicate that bidirectional regulation of HCN2 gating by cGMP contributes to cellular fine-tuning of HCN channel activity.

HCN2 Preparation Options

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