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

Abstract

Shen J-B, Shutt R, Pappano A, Liang BT. Characterization and mechanism of P2X receptor-mediated increase in cardiac myocyte contractility. Am J Physiol Heart Circ Physiol 293: H3056-H3062, 2007. First published September 14, 2007; doi:10.1152/ajpheart.00515.2007.-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 Ca 2ϩ transient effects and to determine the mechanism underlying the receptorinduced increase in myocyte contractility. In response to the agonist 2-methylthioATP (2-meSATP), Tg myocytes showed an increased intracellular Ca 2ϩ transient, as defined by fura 2 fluorescence ratio, and an enhanced contraction shortening that were unaccompanied by cAMP accumulation or L-type Ca 2ϩ channel activation. The increased Ca 2ϩ 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 2ϩ transient. Simultaneous Ca 2ϩ transient and contraction measurements did not show any agonist-mediated change in myofilament Ca 2ϩ sensitivity. However, activation of the overexpressed P2X4 receptor caused an enhanced SR Ca 2ϩ loading, as evidenced by a 2-meSATP-evoked increase in the caffeine-induced inward current and Ca 2ϩ transient. Similar data were obtained in wild-type mouse ventricular myocytes. Thus an increased SR Ca 2ϩ content, occurring in the absence of cAMP accumulation or L-type Ca 2ϩ channel activation, is the principal mechanism by which cardiac P2X receptor mediates a stimulatory effect on cardiac myocyte contractility. purines; calcium; sarcoplasmic reticulum RECEPTORS FOR PURINE NUCLEOTIDES, known as P2 purinergic receptors, are activated by extracellular adenine nucleotides such as ATP and ADP (16,18). The P2 receptor subfamily includes the ligand-gated receptor channel P2X receptor and the G protein-coupled P2Y receptor (1,18,26). Previous studies have shown that extracellular ATP can cause a nonselective cationic current in murine (21), rat (20), and guinea pig (17) cardiac ventricular myocytes. Evidence is accumulating to indicate that the cardiac myocyte P2X receptor mediates this ATP-evoked current. Of the P2X receptor family members, the P2X 4 receptor is an important subunit of the native cardiac myocyte P2X receptor (21). Activation of the P2X receptor leads to the opening of its channel permeable to Na ϩ , K ϩ , and Ca 2ϩ with reversal potential near 0 mV. ATP or the P2X receptor agonist 2-methylthioATP (2-meSATP) can also stimulate an increase in myocyte contractility and in intact heart contractile function (8,15). Transgenic mice with cardiacspecific overexpression of the P2X 4 receptor (Tg) showed an increased myocyte contractility caused by ATP...

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