The 1-Adrenoceptor Subtype- and Protein Kinase C Isoform-dependence of Norepinephrine's Actions in Cardiomyocytes

Author： Rohde S.   Sabri A.   Kamasamudran R.   Steinberg S.F.  

Publisher： Academic Press

ISSN： 0022-2828

Source： Journal of Molecular and Cellular Cardiology, Vol.32, Iss.7, 2000-07, pp. : 1193-1209

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Abstract

Catecholamines modulate cardiac function at least in part through 1-adrenergic receptors linked to the activation of protein kinase C (PKC). This study examines the molecular forms of the1-receptor and PKC that mediate norepinephrine's actions in cardiomyocytes; distinct approaches (activation-dependent down-regulation of PKC isoforms) and novel reagents (A61603, an 1A/c-receptor agonist) are used to resolve this issue which has been the focus of dispute in previous studies. Norepinephrine (NE) induces a rise in diacylglycerol levels which is sustained for 24 h and is associated with the translocation (at 5 min) and down-regulation (at 24 h) of PKC &dgr; and PKC &xgr; (but not PKC ). The selective targeting of the1-adrenergic receptor to activate novel PKC isoforms is remarkable, given an 8-fold greater abundance of PKC relative to PKC &xgr; in this preparation. NE activates the extracellular signal-regulated protein kinase (ERK) subfamily of mitogen-activated protein kinases through a PKC &dgr;/PKC &xgr; -dependent pathway. WB-4101 (1A/c- and 1D-receptor antagonist) and 5-methylurapidil (1A/c-receptor antagonist) inhibit norepinephrine-dependent accumulation of inositol phosphate and diacylglycerol, down-regulation of PKC &dgr; and PKC &xgr;, and activation of ERK. Each of these responses is stimulated by A61603, but not attenuated by high concentrations of chloroethylclonidine (which irreversibly inactivates the1B-, and to a lesser extent, the 1D-receptor) or BMY 7378 (selective1D-receptor antagonist). A61603 also activates p38-MAPK and induces hypertrophy. These studies establish that NE's actions in cardiomyocytes can be attributed to the 1A/c-adrenergic receptor subtype and nPKC isoforms, thereby identifying specific targets for the development of pharmaceuticals to influence cardiac contractile function and/or growth responses.

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