The β-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 (beta(1)-, beta(2)-, and beta(3)-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. Path ophysiology: Stimulation of beta-adrenergic receptors by catecholamines is realized via the beta-adrenoceptor-adenylylcy-clase-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 beta(3)-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 myocard is diminished. It was shown that in these patients the expression of the beta(1)-adrenergic receptor is reduced on the mRNA and protein level. In these patients the expression of the inhibitory G-protein G, 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 beta(1)-adrenergic receptor found in patients with dilated cardiomyopathy. Both, permanent stimulation with catecholamines and chronic treatment with agonistic anti-beta(1)-adrenoceptor autoantibodies cause a reduction of the expression of the beta(1)-adrenoceptor on mRNA and protein level in in vitro experiments. Moreover, an over-expression of the beta(1)-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.