Popeye domain-containing proteins and stress-mediated modulation of cardiac pacemaking

An intricate network of ion channels and pumps are involved in generating a diastolic pacemaker potential, which is transmitted to the working myocardium with the help of the cardiac conduction system. The principles of cardiac pacemaking are reasonably well understood, however, the mechanism by which the heart increases its beating frequency in response to adrenergic stimulation has not been fully worked out. The Popeye domain-containing (Popdc) genes encode plasma membrane-localized proteins that are able to bind cAMP with high affinity; mice with null mutations in Popdc1 or 2 have a stress-induced pacemaker dysfunction. The phenotype in both mutants develops in an age-dependent manner and thus may model pacemaker dysfunction in man, as well as provide novel mechanistic insights into the process of pacemaker adaptation to stress.