PubMed · 2866588
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B Ménégol-Couque, M Brard. [Pre-Par].. https://pubmed.ncbi.nlm.nih.gov/2866588/
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Cardiac hypertrophy and heart failure caused by high blood pressure were studied in single myocytes taken from hypertensive rats (Dahl SS/Jr) and SH-HF rats in heart failure. Confocal microscopy and patch-clamp methods were used to examine excitation-contraction (EC) coupling, and the relation between the plasma membrane calcium current (ICa) and evoked calcium release from the sarcoplasmic reticulum (SR), which was visualized as "calcium sparks." The ability of ICa to trigger calcium release from the SR in both hypertrophied and failing hearts was reduced. Because ICa density and SR calcium-release channels were normal, the defect appears to reside in a change in the relation between SR calcium-release channels and sarcolemmal calcium channels. beta-Adrenergic stimulation largely overcame the defect in hypertrophic but not failing heart cells. Thus, the same defect in EC coupling that develops during hypertrophy may contribute to heart failure when compensatory mechanisms fail.
An important function of the sympathetic nervous system is to maintain homeostasis by modulating the level of cellular activity in many diverse organ systems. The sympathetic neurotransmitter norepinephrine modulates the level of T and B lymphocyte activity by binding to the beta2-adrenergic receptor (beta2AR). The present study was designed to elucidate the mechanism by which stimulation of the beta2AR affects both Th1/Th2 cell cytokine production and Th1/Th2 cell-dependent Ab production. Clones of murine Th1/Th2 cells were exposed to the beta2AR agonist terbutaline before activation by Ag-presenting B cells. Terbutaline exposure of Th1 cells before activation inhibited IFN-gamma production by Th1 cells and subsequent IgG2a production by B cells. IgG2a inhibition was prevented by addition of the betaAR antagonist nadolol or exogenous IFN-gamma. In contrast to Th1 cells, terbutaline did not affect either IL-4 production by Th2 cells or subsequent IgG1 production by B cells. Although baseline levels of intracellular cAMP were similar in both subsets, terbutaline induced an increase in cAMP levels in Th1 cells only. Radioligand binding studies showed that a detectable number of beta2AR binding sites were present on Th1 cells, but not on Th2 cells. Immunofluorescence analyses showed that Th1 cells expressed a higher level of the beta2AR cytoplasmic carboxyl terminus than did Th2 cells. These results show that expression of the beta2AR binding site by Th1 cells, but not by Th2 cells, establishes a physiologic mechanism for selective modulation of Th1 cell IFN-gamma production and IFN-gamma-dependent IgG2a production, provided that beta2AR stimulation occurs before cell activation by a B cell.
The Mr 35,000 beta-adrenergic receptor mRNA-binding protein, termed betaARB protein, is induced by beta-adrenergic agonists and binds to beta2-receptor mRNAs that display agonist-induced destabilization. A cognate sequence in the mRNA was identified previously that provides for betaARB protein binding in vitro. In the present work, the sequence established in vitro for binding of betaARB protein to hamster beta2-adrenergic receptor mRNA was probed in vivo by site-directed mutagenesis of the 3'-untranslated region and expression in Chinese hamster ovary cells. A 20-nucleotide, (A + U)-rich region in the 3'-untranslated region consisting of an AUUUUA hexamer flanked by defined U-rich regions constitutes the binding domain for betaARB protein. U to G substitution in the hexamer region attenuates the binding of betaARB protein, whereas U to G substitution of hexamer and flanking U-rich domains abolishes binding of betaARB protein and stabilizes beta2-adrenergic receptor mRNA levels in transfectant clones challenged with either isoproterenol or cyclic AMP. These results demonstrate that binding of betaARB protein to the 20-nucleotide, (A + U)-rich domain mediates the agonist and cyclic AMP-induced mRNA decay of G protein-linked receptors, such as the beta2-adrenergic receptor.