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.


METHODS
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.
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.
Wallukat
Gerd
G
Max Delbrück Centrum for Moleculare Medicine, Berlin, Germany. gwalluk@mdc-berlin.de
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D001145:Arrhythmias, Cardiac / Q000209:etiology; D001323:Autoantibodies / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000166:cytology; D006333:Heart Failure / Q000209:etiology; D006706:Homeostasis; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D011433:Propranolol / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000276:immunology / Q000502:physiology; D012508:Sarcolemma / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells; D013318:Stroke Volume
D000319:Adrenergic beta-Antagonists; D001323:Autoantibodies; D007074:Immunoglobulin G; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D011433:Propranolol; D002118:Calcium