HCN2 | Potassium/Sodium Hyperpolarization-activated Cyclic Nucleotide-Gated Channel 2
Family:
Hyperpolarization-activated cyclic nucleotide-gated channels
Subgroups:
Four different members HCN1-HCN4
Topology:
The channel protein contains six transmembrane domains (S1–S6), four subunits form a functional channel, homotetramers and heterotetramers
Function:
Nonselective gated cation channels, referred to as pacemaker channels, rhythmicity in brain and heart cells
Background Information HCN2
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, K2P9.1, 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.
Application Notes
HCN2 receptor - "Biophysical modulation of hHCN2 by bPAC recorded on the SyncroPatch 384PE"
SyncroPatch 384PE (a predecessor model of the SyncroPatch 384) application note: 
(1.0 MB)
Cells were engineered and kindly provided by Axxam S.p.A.
Publications
2022 - The suitability of high throughput automated patch clamp for physiological applications
SyncroPatch 384 Publication in The Journal of Physiology (2022)
Authors:
Obergrussberger A., Rinke-Weiß I., Goetze T.A., Rapedius M., Brinkwirth N., Becker N., Rotordam M.G., Hutchison L., Madau P, Pau D, Dalrymple D., Braun N., Friis S., Pless S.A., Fertig N.
2021 - Fragment-Based Design of a Potent MAT2a Inhibitor and in Vivo Evaluation in an MTAP Null Xenograft Model
SyncroPatch 384 Publication in Journal of Medicinal Chemistry (2021)
Authors:
De Fusco C., Schimpl M., Börjesson U., Cheung T., Collie I., Evans L., Narasimhan P., Stubbs C., Vazquez-Chantada M., Wagner D. J., Grondine M., Sanders M. G., Tentarelli S., Underwood E., Argyrou A., Smith J. M., Lynch J. T., Chiarparin E., Robb G., Bagal S. K., Scott J. S.
2019 - Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures
Port-a Patch and Internal Perfusion Publication in JCI Insight (2019)
Authors:
Hammelmann, V., Stieglitz, M.S., Hülle, H., Le Meur, K., Kass, J., Brümmer, M., Gruner, C., Rötzer, R.D., Fenske, S., Hartmann, J., Zott, B., Lüthi, A., Spahn, S., Moser, M,, Isbrandt, D., Ludwig, A., Konnerth, A., Wahl-Schott, C., Biel M.
2012 - Regulation of Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) Channel Activity by cCMP
Port-a-Patch publication in Journal of Biological Chemistry (2012)
Authors:
Zong X., Krause S., Chen C.C., Krüger J., Gruner C., Cao-Ehlker X., Fenske S., Wahl-Schott C., Biel M.