Properties of Hyperpolarization-Activated Pacemaker Current Defined by Coassembly of Hcn1 and Hcn2 Subunits and Basal Modulation by Cyclic Nucleotide
Open accessAbstract
Members of the HCN channel family generate hyperpolarization-activated cation currents (Ih) that are directly regulated by cAMP and contribute to pacemaker activity in heart and brain. The four HCN isoforms show distinct but overlapping patterns of expression in different tissues. Here, we report that HCN1 and HCN2, isoforms coexpressed in neocortex and hippocampus that differ markedly in their biophysical properties, coassemble to generate heteromultimeric channels with novel properties. When expressed in Xenopus oocytes, HCN1 channels activate 5–10-fold more rapidly than HCN2 channels. HCN1 channels also activate at voltages that are 10–20 mV more positive than those required to activate HCN2. In cell-free patches, the steady-state activation curve of HCN1 channels shows a minimal shift in response to cAMP (+4 mV), whereas that of HCN2 channels shows a pronounced shift (+17 mV). Coexpression of HCN1 and HCN2 yields Ih currents that activate with kinetics and a voltage dependence that tend to be intermediate between those of HCN1 and HCN2 homomers, although the coexpressed channels do show a relatively large shift by cAMP (+14 mV). Neither the kinetics, steady-state voltage dependence, nor cAMP dose–response curve for the coexpressed Ih can be reproduced by the linear sum of independent populations of HCN1 and HCN2 homomers. These results are most simply explained by the formation of heteromeric channels with novel properties. The properties of these heteromeric channels closely resemble the properties of Ih in hippocampal CA1 pyramidal neurons, cells that coexpress HCN1 and HCN2. Finally, differences in Ih channel properties recorded in cell-free patches versus intact oocytes are shown to be due, in part, to modulation of Ih by basal levels of cAMP in intact cells.
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cAMP increases the probability that HCN channels will open and allow passage of both Na+ and K+.
“cAMP increases the probability that HCN channels will open93 and allow passage of both Na+ and K+ (this is also referred to as the h current or Ih).”
From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [93]
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- Authors
- Chen, S., Wang, J., & Siegelbaum, S. A.
- Affiliations
- aDepartment of Pharmacology, Molecular, and Biophysical Studies,
- bIntegrated Program in Cellular, Molecular, and Biophysical Studies,
- Howard Hughes Medical Institute (US)
- Venue
- The Journal of General Physiology
- Publisher
- Rockefeller University Press
- Published
- 2001-04-30
- Volume
- 117
- Issue
- 5
- Pages
- 491-504
- ISSN
- 0022-1295 (ISSN-L)
- 1540-7748
- PMC
- PMC2233656
- OpenAlex
- W1988174768
- Cited by
- 416
- References
- 1
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 7 · 2023: 12 · 2022: 12 · 2021: 13 · 2020: 13 · 2019: 11 · 2018: 11 · 2017: 9 · 2016: 13 · 2015: 13 · 2014: 12 · 2013: 16 · 2012: 24
- FWCI
- 8.12
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of General Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS036658)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- hyperpolarization-activated current, HCN1, HCN2, HCN channels, heteromeric channels, channel gating kinetics, voltage dependence of activation, CA1 pyramidal neurons, pacemaker activity, neocortex, brain pacemaker
- MeSH terms
- Cyclic AMP, Animals, Binding Sites, Biological Clocks, Dose-Response Relationship, Drug, Ion Channels, Membrane Potentials, Muscle Proteins, Nerve Tissue Proteins, Oocytes, Xenopus, Potassium Channels, Ion Channel Gating, Mutagenesis, Site-Directed, Point Mutation, Patch-Clamp Techniques, Mice, Cyclic Nucleotide-Gated Cation Channels, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
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