SPOTLIGHT REVIEW Spatial control of the bAR system in heart failure: the transverse tubule and beyond

The beta1-adrenoceptors (b1AR) and beta-2 (b2AR) adrenoceptors represent the predominant pathway for sympathetic control of myocardial function. Diverse mechanisms have evolved to translate signalling via these two molecules into differential effects on physiology. In this review, we discuss how the functions of the bAR are organized from the level of secondary messengers to the whole heart to achieve this. Using novel microscopy and bioimaging methods researchers have uncovered subtle organization of the control of cyclic adenosine monophosphate (cAMP), the predominant positively inotropic pathway for the bAR. The b2AR in particular is demonstrated to give rise to highly compartmentalized, spatially confined cAMP signals. Organization of b2AR within the T-tubule and caveolae of cardiomyocytes concentrates this receptor with molecules which buffer and shape its cAMP signal to give fine control. This situation is undermined in various forms of heart failure. Human and animal models of heart failure demonstrate disruption of cellular micro-architecture which contributes to the change in response to cardiac bARs. Loss of cellular structure has proved key to the observed loss of confined b2AR signalling. Some pharmacological and genetic treatments have been successful in returning failing cells to a more structured phenotype. Within these cells it has been possible to observe the partial restoration of normal b2AR signalling. At the level of the organ, the expression of the two bAR subtypes varies between regions with the b2AR forming a greater proportion of the bAR population at the apex. This distribution may contribute to regional wall motion abnormalities in Takotsubo cardiomyopathy, a syndrome of high sympathetic activity, where the phosphorylated b2AR can signal via Gi protein to produce negatively inotropic effects.