Characterization and mechanism of P2X receptor-mediated increase in cardiac myocyte contractility

Cardiac P2X purinergic receptors can mediate an increase in myocyte contractility and a potentially important role in the heart. The P2X(4) receptor (P2X(4)R) is an important subunit of native cardiac P2X receptors. With transgenic mice with cardiac-specific overexpression of P2X(4)R (Tg) used as a model, the objectives here were to characterize the P2X receptor-mediated cellular contractile and Ca(2+) transient effects and to determine the mechanism underlying the receptor-induced increase in myocyte contractility. In response to the agonist 2-methylthioATP (2-meSATP), Tg myocytes showed an increased intracellular Ca(2+) transient, as defined by fura 2 fluorescence ratio, and an enhanced contraction shortening that were unaccompanied by cAMP accumulation or L-type Ca(2+) channel activation. The increased Ca(2+) transient was not associated with any alteration in action potential duration, resting membrane potential, or diastolic fluorescence ratio or rates of rise and decline of the Ca(2+) transient. Simultaneous Ca(2+) transient and contraction measurements did not show any agonist-mediated change in myofilament Ca(2+) sensitivity. However, activation of the overexpressed P2X(4) receptor caused an enhanced SR Ca(2+) loading, as evidenced by a 2-meSATP-evoked increase in the caffeine-induced inward current and Ca(2+) transient. Similar data were obtained in wild-type mouse ventricular myocytes. Thus an increased SR Ca(2+) content, occurring in the absence of cAMP accumulation or L-type Ca(2+) channel activation, is the principal mechanism by which cardiac P2X receptor mediates a stimulatory effect on cardiac myocyte contractility.