Modulation of human cardiac function through 4 beta-adrenoceptor populations.
In human heart there is now evidence for the involvement of four beta-adrenoceptor populations, three identical to the recombinant beta 1-, beta 2- and beta 3-adrenoceptors, and a fourth as yet uncloned putative beta-adrenoceptor population, which we designate provisionally as the cardiac putative beta 4-adrenoceptor. This review described novel features of beta-adrenoceptors as modulators of cardiac systolic and diastolic function. We also discuss evidence for modulation by unoccupied beta 1- and beta 2-adrenoceptors. Human cardiac and recombinant beta 1- and beta 2-adrenoceptors are both mainly coupled to adenylyl cyclase through Gs protein, the latter more tightly than the former. Activation of both human beta 1- and beta 2-adrenoceptors not only increases cardiac force during systole but also hastens relaxation through cyclic AMP-dependent phosphorylation of phospholamban and troponin 1, thereby facilitating diastolic function. Furthermore, both beta 1 and beta 2-adrenoceptors can mediate experimental arrhythmias in human cardiac preparations elicited by noradrenaline and adrenaline. Human ventricular beta 3-adrenoceptors appear to be coupled to a pertussis toxin-sensitive protein (Gi?). beta 3-Adrenoceptor-selective agonists shorten the action potential and cause cardiodepression, suggesting direct coupling of a Gi protein to a K+ channel. In a variety of species, including man, cardiac putative beta 4-adrenoceptors mediate cardiostimulant effects of non-conventional partial agonists, i.e. high affinity beta 1- and beta 2-adrenoceptor blockers that cause agonist effects at concentrations considerably higher than those that block these receptors. Putative beta 4-adrenoceptors appear to be coupled positively to a cyclic AMP-dependent cascade and can undergo some desensitisation.
Kaumann
A J
AJ
Babraham Institute, Human Pharmacology Laboratory, Cambridge, UK.
Molenaar
P
P
D016275:Atrial Function; D003971:Diastole; D006321:Heart / Q000502:physiology*; D006801:Humans; D009200:Myocardial Contraction; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology; D022702:Receptors, Adrenergic, beta-3; D013599:Systole
D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3