Cardiac P2X purinergic receptors as a new pathway for increasing Na⁺ entry in cardiac myocytes.

P2X4 receptors (P2X4Rs) are ligand-gated ion channels capable of conducting cations such as Na(+). Endogenous cardiac P2X4R can mediate ATP-activated current in adult murine cardiomyocytes. In the present study, we tested the hypothesis that cardiac P2X receptors can induce Na(+) entry and modulate Na(+) handling.

Treatment of heart failure by a methanocarba derivative of adenosine monophosphate: implication for a role of cardiac purinergic P2X receptors.

Evidence is accumulating to support a potentially important role for purinergic (P2X) receptors in heart failure (HF). We tested the hypothesis that a hydrolysis-resistant nucleotide analog with agonist activity at myocardial P2X receptors (P2XRs) improves the systolic HF phenotype in mouse and dog models. We developed a hydrolysis-resistant adenosine monophosphate derivative, (1'S,2R,3S,4'R,5'S)-4-(6-amino-2-chloro-9H-purin-9-yl)-1-[phosphoryloxymethyl] bicycle[3.

Reversal of cardiac myocyte dysfunction as a unique mechanism of rescue by P2X4 receptors in cardiomyopathy.

Binary cardiac transgenic (Tg) overexpression of P2X(4) receptors (P2X(4)R) improved the survival of the cardiomyopathic calsequestrin (CSQ) mice. Here we studied the mechanism of rescue using binary P2X(4)R/CSQ Tg and CSQ Tg mice as models. Cellular and intact heart properties were determined by simultaneous sarcomere shortening (SS) and Ca(2+) transients in vitro and echocardiography in vivo.

Role of P2X purinergic receptors in the rescue of ischemic heart failure.

Evidence is accumulating to support the presence of P2X purinergic receptors in the heart. However, the biological role of this receptor remains to be defined. The objectives here were to determine the role of cardiac P2X receptors in modulating the progression of post-myocardial infarction ischemic heart failure and to investigate the underlying mechanism.

An estrogen metabolite, 2-methoxyestradiol, disrupts cardiac microtubules and unmasks muscarinic inhibition of calcium current.

Microtubules provide a chemical signaling function as well as structural support for heart cells. Microtubules modulate autonomic signaling in the heart, and their disruption by colchicine unmasks muscarinic inhibition of Ca (ICa) current. In this study, we compare the actions of the estrogen metabolite, 2-methoxyestradiol (2-ME), with those of colchicine on microtubule stability and chemical signal function in guinea pig-isolated ventricular myocytes.

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.

Extracellular ATP-stimulated current in wild-type and P2X4 receptor transgenic mouse ventricular myocytes: implications for a cardiac physiologic role of P2X4 receptors.

P2X receptors, activated by extracellular ATP, may be important in regulating cardiac function. The objective of the present study was to characterize the electrophysiologic actions of P2X4 receptors in cardiac myocytes and to determine whether they are involved in mediating the effect of extracellular ATP. Membrane currents under voltage clamp were determined in myocytes from both wild-type (WT) and P2X4 receptor-overexpressing transgenic (TG) mice.

Autonomic regulation of calcium and potassium channels is oppositely modulated by microtubules in cardiac myocytes.

We recently showed that colchicine treatment of rat ventricular myocytes increases the L-type Ca2+ current (I(Ca)) and intracellular Ca2+ concentration ([Ca2+](i)) transients and interferes with adrenergic signaling. These actions were ascribed to adenylyl cyclase (AC) stimulation after G(s) activation by alpha,beta-tubulin. Colchicine depolymerizes microtubules into alpha,beta-tubulin dimers.

On the role of phosphatase in regulation of cardiac L-type calcium current by cyclic GMP.

Does cGMP, via protein kinase G, inhibit cAMP-stimulated Ca(2+) current (I(Ca(L))) in mammalian ventricular myocytes by phosphorylating the calcium channel at a site different from that acted on by cAMP or by dephosphorylating the calcium channel through phosphatase(s)? We tested these possibilities in guinea pig ventricular myocytes superfused with Tyrode's solution (35 degrees C) and dialyzed with adenosine 5'-O-(3-thiotriphosphate) ([ATPgammaS](pip)). ATPgammaS is a kinase substrate but thiophosphorylated proteins are not phosphatase substrates. With 5 mM [ATPgammaS](pip), I(Ca(L)) increased gradually over 20 to 25 min and then rapidly in the presence of 3-isobutyl-1-methylxanthine.