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Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2014 Oct 07; Vol. 111 (40), pp. 14577-82. Date of Electronic Publication: 2014 Sep 02. - Publication Year :
- 2014
-
Abstract
- cAMP signaling in the brain mediates several higher order neural processes. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels directly bind cAMP through their cytoplasmic cyclic nucleotide binding domain (CNBD), thus playing a unique role in brain function. Neuronal HCN channels are also regulated by tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), an auxiliary subunit that antagonizes the effects of cAMP by interacting with the channel CNBD. To unravel the molecular mechanisms underlying the dual regulation of HCN channel activity by cAMP/TRIP8b, we determined the NMR solution structure of the HCN2 channel CNBD in the cAMP-free form and mapped on it the TRIP8b interaction site. We reconstruct here the full conformational changes induced by cAMP binding to the HCN channel CNBD. Our results show that TRIP8b does not compete with cAMP for the same binding region; rather, it exerts its inhibitory action through an allosteric mechanism, preventing the cAMP-induced conformational changes in the HCN channel CNBD.
- Subjects :
- Binding Sites
Crystallography, X-Ray
Cyclic AMP metabolism
Cyclic Nucleotide-Gated Cation Channels chemistry
Cyclic Nucleotide-Gated Cation Channels metabolism
Electrophoresis, Polyacrylamide Gel
Humans
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels metabolism
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Structure
Potassium Channels chemistry
Potassium Channels metabolism
Protein Binding
Protein Structure, Secondary
Protein Structure, Tertiary
Receptors, Cytoplasmic and Nuclear metabolism
Cyclic AMP chemistry
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels chemistry
Ion Channel Gating
Receptors, Cytoplasmic and Nuclear chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 111
- Issue :
- 40
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 25197093
- Full Text :
- https://doi.org/10.1073/pnas.1410389111