Referenced in: none

Automatically associated channels: HCN2

Title: Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function.

Authors: Andrea Saponaro, Sofia R Pauleta, Francesca Cantini, Manolis Matzapetakis, Christian Hammann, Chiara Donadoni, Lei Hu, Gerhard Thiel, Lucia Banci, Bina Santoro, Anna Moroni

Journal, date & volume: Proc. Natl. Acad. Sci. U.S.A., 2014 Oct 7 , 111, 14577-82

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25197093

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.