Minimal molecular determinants of isoform-specific differences in efficacy in the HCN channel family.

ABSTRACT: Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate rhythmic activity in the heart and brain. Isoform-specific functional differences reflect the specializations required for the various roles that they play. Despite a high sequence and structural similarity, HCN isoforms differ greatly in their response to cyclic nucleotides. Cyclic AMP (cAMP) enhances the activity of HCN2 and HCN4 isoforms by shifting the voltage dependence of activation to more depolarized potentials, whereas HCN1 and HCN3 isoforms are practically insensitive to this ligand. Here, to determine the molecular basis for increased cAMP efficacy in HCN2 channels, we progressively mutate residues in the C-linker and cyclic nucleotide-binding domain (CNBD) of the mouse HCN2 to their equivalents in HCN1

SUBMITTER: Alvarez-Baron CP 

PROVIDER: S-EPMC6080897 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature