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

With use of the whole cell patch-clamp technique, effects of the potent muscarinic agonist oxotremorine methiodide (oxo-M) on voltage-activated Ca2+ channel currents were investigated in acutely dissociated adult rat intracardiac neurons. In all tested neurons oxo-M reversibly inhibited the peak Ba2+ current. Inhibition of the peak Ba2+ current by oxo-M was associated with slowing of activation kinetics and was concentration dependent. The concentration of oxo-M necessary to produce a half-maximal inhibition of current and the maximal inhibition were 40.8 nM and 75.9%, respectively. Inhibitory effect of oxo-M was completely abolished by atropine. Among different muscarinic receptor antagonists, methoctramine (100 and 300 nM) significantly antagonized the current inhibition by oxo-M, with a negative logarithm of dissociation constant of 8.3 in adult rat intracardiac neurons. Internal dialysis of neurons with guanosine 5'-(thio)triphosphate (GTPgammaS, 0.5 mM) could mimic the muscarinic inhibition of the peak Ba2+ current and significantly occlude inhibitory effects of oxo-M. In addition, the internal dialysis of guanosine-5'-O-(2-thiodiphosphate) (GDPbetaS, 2 mM) also significantly reduced the muscarinic inhibition of the peak Ba2+ current by oxo-M. Inhibitory effects of oxo-M were significantly abolished by pertussis toxin (PTX, 200 and 400 ng/ml) but not by cholera toxin (400 ng/ml). Furthermore, the bath application of N-ethylmaleimide (50 microM) significantly reduced the inhibition of the peak Ba2+ current by oxo-M. The oxo-M shifted the activation curve derived from measurments of tail currents toward more positive potentials. A strong conditioning prepulse to +100 mV significantly relieved the muscarinic inhibition of peak Ba2+ currents by oxo-M and the GTPgammaS-induced current inhibition. In a series of experiments, changes in intracellular concentration of bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid and protein kinase activities failed to mimic or occlude the current inhibition by oxo-M. The dihydropyridine antagonist nifedipine (10 microM) was not able to occlude any of the inhibitory effects of oxo-M, and oxo-M (3 microM) failed to reduce the slow tail currents induced by the L-type agonist methyl 2,5-dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylate (FPL 64176; 2 microM). However, omega-conotoxin (omega-CgTX) GVIA (1 microM) significantly occluded the muscarinic inhibition of the Ba2+ currents. In the presence of omega-CgTX GVIA (1 microM) and nifedipine (10 microM), oxo-M could further inhibit approximately 20% of the total Ca2+ current. After complete removal of N-, Q-, and L-type currents with use of omega-CgTX GVIA, omega-agatoxin IVA, and nifedipine, 70% of the R-type current (approximately 6-7% of the total current) was inhibited by oxo-M (3 microM). In conclusion, the M2 muscarinic receptor activation selectively inhibits N-, Q-, and R-type Ca2+ channel currents, sparing L-type Ca2+ channel currents mainly via a PTX- and voltage-sensitive pathway in adult rat intracardiac neurons.
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PMID:Muscarinic receptor activation modulates Ca2+ channels in rat intracardiac neurons via a PTX- and voltage-sensitive pathway. 931 Apr 37

Coexpression of Y1, Y2, and Y4 receptors on smooth muscle cells was determined by reverse transcription-polymerase chain reaction, and the receptors were characterized by radioligand binding, selective receptor protection, and functional analysis of signaling pathways. 125I-peptide YY (PYY) binding was completely inhibited by neuropeptide Y (NPY) and PYY, and partially inhibited by the Y1 agonist [Leu31, Pro34]NPY or the Y2 agonist NPY13-36. In cells where Y1 receptors were preserved by selective receptor protection, 125I-PYY binding was selectively inhibited by the Y1 agonist or antagonist BIBP 3226 [(R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-D-arginine-amide]. Conversely, in cells where Y2 receptors were preserved, 125I-PYY binding was selectively inhibited by the Y2 agonist or antagonist BIIE 0246 [(S)N2-[1-[2-[4-[(R,S)-5,11-dihydro-6(66H)-oxodibenz[b,e]azepin-11-y]-1piperazinyl]-2-oxoethyl]cyclopentyl]acetyl]-N-[2-[1,2-dihydro-35(4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamide]. All Y receptors activated preferentially Gi2, but only Y2 and Y4 receptors activated Gq. Consequently, Y2 agonists (NPY, PYY, and NPY13-36) and the Y4 agonist (pancreatic polypeptide) induced concentration-dependent contraction, inositol 1,4,5-trisphosphate (IP3) formation, and increase in cytosolic free Ca2+. Contraction induced by Y2 and Y4 agonists was not affected by 0 Ca2+, Ca2+ channel blockers, or pertussis toxin (PTx), but it was abolished by thapsigargin, U73122 [1-(6-(17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-25-dione], or the myosin light chain kinase inhibitor ML-9 [1-(5-chloronaphthalene-1-sulfonyl)homopiperazine, HCl]. Y2-mediated contraction was inhibited by the selective Y2 antagonist BIIE 0246. Insensitivity to PTx implied that the coupling to Gi did not initiate (Y1) or contribute (Y2 and Y4) to contraction. All Y receptor agonists inhibited cAMP formation in a PTx-sensitive manner. The patterns of contraction and inhibition of cAMP by various Y receptors were corroborated by selective receptor protection. The study demonstrates coexpression of Y1, Y2, and Y4 receptors on smooth muscle negatively coupled to adenylyl cyclase via Gi2. Coupling of Y2 and Y4 receptors to Gq determines their ability to induce IP3-dependent Ca2+ release and initiate contraction.
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PMID:Coexpression of Y1, Y2, and Y4 receptors in smooth muscle coupled to distinct signaling pathways. 1530 51