Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased Na+/Ca(2+)-exchanger (NCX) and altered beta-adrenoceptor (betaAR) responses are observed in failing human heart. To determine the possible interaction between these changes, we investigated the effect of NCX overexpression on responses to isoproterenol in adult rat ventricular myocytes. Responses to isoproterenol were largely mediated through the beta1AR in control myocytes. Adenovirally-mediated overexpression of NCX, at levels, which did not alter basal contraction of myocytes, markedly depressed the isoproterenol concentration-response curve. Responses to isoproterenol could be restored to normal by beta2AR blockade, suggesting a beta2AR-mediated inhibition of beta1AR signalling. Pertussis toxin normalised isoproterenol responses in NCX cells, indicating that beta2AR effects were mediated by Gi. Negative-inotropic effects of high concentrations of ICI 118,551, previously shown to be due to beta2AR-Gi coupling, were increased in NCX cells. We conclude that NCX upregulation can markedly alter the consequences of betaAR stimulation and that this may contribute to the alterations in betaAR response seen in failing human heart.
 ...
PMID:Loss of beta-adrenoceptor response in myocytes overexpressing the Na+/Ca(2+)-exchanger. 1473 40

Intracellular calcium signaling cascade induced by adenosine A(3) receptor activation was studied in this work. It was found that adenosine A(3) receptor activation (and not A(1) or A(2A) adenosine receptors activation) leads to an increase in cytosolic calcium and its further extrusion. A selective A(3) agonist Cl-IB-MECA (2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide) induced an increase in cytoplasmic calcium in a dose-dependent manner, and was independent on extracellular calcium. The Ca(2+) signal in newborn cardiomyocytes, induced by A(3) receptor activation, is dependent on a pertussis toxin-sensitive G-protein. The action of Cl-IB-MECA was not inhibited by an inhibitor of phospholipase C (PLC), and by antagonists to inositol 1,4,5-trisphosphate (IP(3)) receptor. In contrast, inhibition of ryanodine receptor prevented calcium elevation induced by this agonist. It was shown that extrusion of the elevated cytosolic Ca(2+) was achieved via activation of sarcoplasmic reticulum (SR) Ca(2+)-reuptake and of sarcolemmal Na(+)/Ca(2+) exchanger (NCX). The increase in the SR Ca(2+)-uptake and NCX Ca(2+) efflux were sufficient not only for compensation of Ca(2+) release from SR after A(3) receptor activation, but also for an effective prevention of extensive increase in intracellular Ca(2+) and may provide mechanism against cellular Ca(2+) overload. In cells with elevated [Ca(2+)](i) (due to increase of [Ca(2+)](o)), adenosine or Cl-IB-MECA decreased the [Ca(2+)](i) toward diastolic control level, whereas agonist of A(1) receptor was ineffective. The protective effect of A(3) receptor agonist was abolished in the presence of selective A(3) receptor antagonist MRS1523.
 ...
PMID:Analysis of calcium responses mediated by the A3 adenosine receptor in cultured newborn rat cardiac myocytes. 1545 22

Using the whole-cell voltage clamp, we examined the mechanism of activation of the Na(+)/Ca(2+) exchanger (NCX) by hydrogen peroxide (H(2)O(2)) in isolated guinea-pig cardiac ventricular myocytes. Exposure to H(2)O(2) increased the NCX current. The effect was inhibited by cariporide, an inhibitor of the Na(+)/H(+) exchanger (NHE), suggesting that there are NHE-dependent and -independent pathways in the effect of H(2)O(2) on NCX. In addition, both pathways were blocked by edaravone, a hydroxyl radical (*OH) scavenger; pertussis toxin, a Galpha(i/o) protein inhibitor; and U0126, an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK). On the other hand, wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor, inhibited only the NHE-dependent pathway, while PP2, a Src family protein tyrosine kinase inhibitor, inhibited only the NHE-independent pathway. Taken together, our data suggest that H(2)O(2) increases the NCX current via two signal transduction pathways. The common pathway is the conversion of H(2)O(2) to *OH, which activates Galpha(i/o) protein and a mitogen-activated protein (MAP) kinase signaling pathway. Then, one pathway activates NHE with a PI3K-dependent mechanism and indirectly increases the NCX current. Another pathway involves activation of a Src family tyrosine kinase.
 ...
PMID:Mechanism of Na+/Ca2+ exchanger activation by hydrogen peroxide in guinea-pig ventricular myocytes. 1733 93

Prior studies indicate that cholinergic receptor (ChR) activation is linked to beating rate reduction (BRR) in sinoatrial nodal cells (SANC) via 1) a G(i)-coupled reduction in adenylyl cyclase (AC) activity, leading to a reduction of cAMP or protein kinase A (PKA) modulation of hyperpolarization-activated current (I(f)) or L-type Ca(2+) currents (I(Ca,L)), respectively; and 2) direct G(i)-coupled activation of ACh-activated potassium current (I(KACh)). More recent studies, however, have indicated that Ca(2+) cycling by the sarcoplasmic reticulum within SANC (referred to as a Ca(2+) clock) generates rhythmic, spontaneous local Ca(2+) releases (LCR) that are AC-PKA dependent. LCRs activate Na(+)-Ca(2+) exchange (NCX) current, which ignites the surface membrane ion channels to effect an AP. The purpose of the present study was to determine how ChR signaling initiated by a cholinergic agonist, carbachol (CCh), affects AC, cAMP, and PKA or sarcolemmal ion channels and LCRs and how these effects become integrated to generate the net response to a given intensity of ChR stimulation in single, isolated rabbit SANC. The threshold CCh concentration ([CCh]) for BRR was approximately 10 nM, half maximal inhibition (IC(50)) was achieved at 100 nM, and 1,000 nM stopped spontaneous beating. G(i) inhibition by pertussis toxin blocked all CCh effects on BRR. Using specific ion channel blockers, we established that I(f) blockade did not affect BRR at any [CCh] and that I(KACh) activation, evidenced by hyperpolarization, first became apparent at [CCh] > 30 nM. At IC(50), CCh reduced cAMP and reduced PKA-dependent phospholamban (PLB) phosphorylation by approximately 50%. The dose response of BRR to CCh in the presence of I(KACh) blockade by a specific inhibitor, tertiapin Q, mirrored that of CCh to reduced PLB phosphorylation. At IC(50), CCh caused a time-dependent reduction in the number and size of LCRs and a time dependent increase in LCR period that paralleled coincident BRR. The phosphatase inhibitor calyculin A reversed the effect of IC(50) CCh on SANC LCRs and BRR. Numerical model simulations demonstrated that Ca(2+) cycling is integrated into the cholinergic modulation of BRR via LCR-induced activation of NCX current, providing theoretical support for the experimental findings. Thus ChR stimulation-induced BRR is entirely dependent on G(i) activation and the extent of G(i) coupling to Ca(2+) cycling via PKA signaling or to I(KACh): at low [CCh], I(KACh) activation is not evident and BRR is attributable to a suppression of cAMP-mediated, PKA-dependent Ca(2+) signaling; as [CCh] increases beyond 30 nM, a tight coupling between suppression of PKA-dependent Ca(2+) signaling and I(KACh) activation underlies a more pronounced BRR.
 ...
PMID:Cholinergic receptor signaling modulates spontaneous firing of sinoatrial nodal cells via integrated effects on PKA-dependent Ca(2+) cycling and I(KACh). 1954 82