A novel contractile phenotype with cardiac transgenic expression of the human P2X(4) receptor

The P2X(4) receptor is a newly identified receptor expressed in the heart c ell. Its function was elucidated with cardiac transgenic (TG) expression of the receptor by using the myocardium-specific alpha -myosin heavy chain pr omoter. The presence of the transgene was determined by polymerase chain re action by using primers specific to the receptor and the vector linker regi on, by Southern blotting of the genomic DNA, and by immunoblotting and immu nohistochemistry of both isolated cardiac myocytes and intact hearts. In in tact heart study, the P2X(4) receptor TG mouse exhibited significantly elev ated basal cardiac contractility with greater rates of contraction and rela xation, left ventricular developed pressure, and cardiac output compared wi th nontransgenic (NTG) animals but showed no evidence of hypertrophy or hea rt failure. The TG heart also showed a greater increase of cardiac contract ility in response to the P2X receptor agonist 2-methylthioATP, consistent w ith overexpression of a functional P2X(4) receptor with consequent increase in the receptor-mediated response. In isolated cardiac cell study, the TG heart cell showed a similar level of basal contraction amplitude as the NTG heart cell while exhibiting a threefold greater increase in contractility during stimulation by 2-methylthioATP. Thus, an increased responsiveness of the overexpressed P2X(4) receptor to endogenous ATP is responsible for the enhanced basal cardiac performance in the intact TG heart. The sustained e nhanced contractile function with no associated heart pathology in the P2X( 4) receptor TG mouse suggests a novel physiologic role of the P2X(4) recept or, that of stimulating the cardiac contractility.