Impact of micronutrient supplementation during pregnancy on birth weight, duration of gestation, and perinatal mortality in rural western China: double blind cluster randomised controlled trial

Abstract

The auxiliary subunit TRIP8b prevents cAMP activation of HCN channels by antagonizing its binding to their cyclic-nucleotide binding domain (CNBD). By determining an NMR-derived structure of the complex formed by the HCN2 channel CNBD and a minimal TRIP8b fragment, TRIP_nano, we show here a bipartite interaction between the peptide and CNBD which prevents cAMP binding in two ways: through direct competition for binding at the distal C-helix of the CNBD; and through an allosteric reduction in cAMP affinity induced by TRIP8b binding to the CNBD N-bundle loop. TRIP_nano abolishes cAMP binding in all three isoforms, HCN1, HCN2 and HCN4 and can be used to prevent cAMP stimulation in native f-channels. Application of TRIP8b_nano, or its delivery via a cell-penetrating sequence, in sinoatrial node myocytes, selectively inhibits beta-adrenergic stimulation of the native I_f current and mimics the physiological concentrations of acetylcholine leading to a 30% reduction in the spontaneus rate of action potential firing.