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 P2X4 receptor (P2X4R) is an important subunit of native cardiac P2X receptors. With transgenic mice with cardiac-specific overexpression of P2X4R (Tg) used as a model, the objectives here were to characterize the P2X receptor-mediated cellular contractile and Ca2+ 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 Ca2+ transient, as defined by fura 2 fluorescence ratio, and an enhanced contraction shortening that were unaccompanied by cAMP accumulation or L-type Ca2+ channel activation. The increased Ca2+ 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 Ca2+ transient. Simultaneous Ca2+ transient and contraction measurements did not show any agonist-mediated change in myofilament Ca2+ sensitivity. However, activation of the overexpressed P2X4 receptor caused an enhanced SR Ca2+ loading, as evidenced by a 2-meSATP-evoked increase in the caffeine-induced inward current and Ca2+ transient. Similar data were obtained in wild-type mouse ventricular myocytes. Thus an increased SR Ca2+ content, occurring in the absence of cAMP accumulation or L-type Ca2+ channel activation, is the principal mechanism by which cardiac P2X receptor mediates a stimulatory effect on cardiac myocyte contractility.