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  • Title: Alpha 1-adrenergic and H1-histamine receptor control of intracellular Ca2+ in a muscle cell line: the influence of prior agonist exposure on receptor responsiveness.
    Author: Brown RD, Prendiville P, Cain C.
    Journal: Mol Pharmacol; 1986 Jun; 29(6):531-9. PubMed ID: 2872587.
    Abstract:
    Activation of alpha 1-adrenergic receptors in BC3H-1 muscle cells has been shown previously to mobilize intracellular Ca2+, which can be monitored as enhanced 45Ca2+ unidirectional efflux. We report here that histamine also stimulates 45Ca2+ efflux in these cells (Kact = 5.50 microM, nH = 0.94 +/- 0.04), reflecting mobilization of intracellular Ca2+ from a source similar to that accessed by alpha 1-adrenergic receptor activation. In addition, histamine stimulates substantial transmembrane 45Ca2+ influx into BC3H-1 cells. The actions of histamine are inhibited by the H1-selective antagonist, diphenhydramine (IC50 = 1.01 microM), but are unaffected by the H2-selective antagonist, cimetidine (1 nM-10 microM) indicating that histamine regulates cellular Ca2+ via a functional H1 receptor. The presence of independent receptor types which mobilize Ca2+ originating from common intracellular stores has been exploited in order to evaluate the determinants of receptor responsiveness following prior agonist exposure. After exposure with 45Ca2+ to achieve radioisotopic equilibrium, 30 min incubation with increasing concentrations of norepinephrine reduces to similar extents (30-40%) the unidirectional 45Ca2+ efflux responses to subsequent challenges by maximally effective concentrations of norepinephrine or histamine. The decrement in response following norepinephrine exposure appears to reflect an altered disposition of agonist-sensitive intracellular Ca2+, whereas the concentration dependence for alpha 1-adrenergic receptor activation remains unchanged. Prior exposure of cells to increasing concentrations of histamine also reduces the efflux response to norepinephrine challenge (approximately 30% decrease), whereas the response to subsequent histamine challenge is specifically and completely abolished. The loss of histamine responsiveness is accompanied by a marked shift in the concentration dependence for histamine receptor activation toward higher histamine concentrations. These results indicate that substantial alpha 1-receptor responsiveness is maintained following agonist exposure and that the observed reduction in response occurs distally to the receptor itself at some point common to alpha 1- and H1-receptor-effector coupling. By contrast, the H1-histamine receptor exhibits refractoriness, indicative of agonist-induced receptor desensitization.
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