HCN2 | Potassium/Sodium Hyperpolarization-activated Cyclic Nucleotide-Gated Channel 2

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2 (also called BCNG2) is a protein that in humans is encoded by the HCN2 gene. The channel is involved in the generation of native pacemaker activity in the heart and in the brain. It activates upon hyperpolarization, exhibiting weak selectivity for potassium over sodium ions. It produces a large instantaneous current and is modulated by intracellular chloride ions and acidic pH. HCN2 is activated by cAMP, and at 10-100 times higher concentrations, also by cGMP. cAMP binding causes a conformation change that leads to the assembly of an active tetramer and channel opening. Together with HCN4, HCN2 is the dominant form of HCN expressed in the heart.

Gene:
HCN2

Human Protein:
UniProt Q9UL51

Tissue:
Highly expressed throughout the brain. Detected at low levels in heart.

Function/ Application:
Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). It can also transport ammonium in the distal nephron.

Pathology:
Epilepsy, Retinitis Pigmentosa 25, Frontotemporal dementia, cardiomyopathy (diluted 1u), acne inversa (familial, 3), pick disease of the brain, Brugada syndrome, Sick sinus syndrome 2 (SSS2), Parkinson's disease

Interaction:
Forms heterotetramers with HCN1 and HCN4. Forms an obligate 4:4 complex with accessory subunit PEX5L. Interacts with KCNE2, KCR1, K_2P9.1, Protein kinase G 2, tamalin, C-terminal Src kinase

Modulator:
cyclic AMP, ivabradine, cilobradine, ZD 7288, zatebradine hydrochloride, clonidine, Cs⁺, Mg⁺

Assays:
Patch Clamp: whole cell including temperature control and internal perfusion

Recommended Reviews:
Becirovic E. et al. (2019) Cyclic nucleotide-regulated channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database.