The beta-adrenergic receptors.

BACKGROUND

The beta-adrenergic receptors of the myocardium play an important role in the regulation of heart function. The beta-adrenergic receptors belong to the family of G-protein coupled receptors. Three subtypes have been distinguished (beta1-, beta2-, and beta3-adrenoceptors). The receptors consist of seven membrane-spanning domains, three intra- and three extracellular loops, one extracellular N-terminal domain, and one intracellular C-terminal tail.

PATHOPHYSIOLOGY

Stimulation of beta-adrenergic receptors by catecholamines is realized via the beta-adrenoceptor-adenylylcyclase-protein kinase A cascade. The second messenger is the cyclic AMP (cAMP). Stimulation of the cascade caused an accumulation of the second messenger cAMP and activated via the cAMP the cAMP dependent protein kinase A (PKA) The PKA phosphorylated, beside other cell proteins, the beta-adrenergic receptors. A phosphorylation of the beta-adrenergic receptors caused - with exception of the beta3-adrenoceptor - an uncoupling and desensitisation of the receptors. Phosphorylation via the G-protein receptor kinase (GRK or betaARK) also caused uncoupling and reduced the beta-adrenergic responsiveness. The uncoupling of the receptor is the prerequisite for receptor internalisation. In the process of internalisation the receptor shifted from the sarcolemma membrane into cytosolic compartments. Chronic beta-adrenergic stimulation caused a down-regulation of the receptors. During this process of desensitisation the expression of the receptor on mRNA and protein level is reduced.

CHANGING OF THE RECEPTORS IN THE FAILING HEART

In patients with dilated cardiomyopathy the beta-adrenergic responsiveness of the myocardium is diminished. It was shown that in these patients the expression of the beta1-adrenergic receptor is reduced on the mRNA and protein level. In these patients the expression of the inhibitory G-protein G(i) is increased. Furthermore, the expression of the G-protein receptor kinase is elevated. This kinase induces the uncoupling of the beta-adrenergic receptors. These alterations of the beta-adrenoceptor signal cascade may be induced by an elevated catecholamine release or by agonist-like autoantibodies directed against the beta1-adrenergic receptor found in patients with dilated cardiomyopathy. Both, permanent stimulation with catecholamines and chronic treatment with agonistic anti-beta1-adrenoceptor autoantibodies cause a reduction of the expression of the beta1-adrenoceptor on mRNA and protein level in "in vitro" experiments. Moreover, an over-expression of the beta1-adrenoceptor, the stimulatory G(s) protein, and the protein kinase A induce detrimental alterations of the cardiac function and morphology in transgenic animals. These animals developed heart failure accompanied by an increased mortality rate.