β-Adrenergic receptors and their interacting proteins

Abstract

The three subtypes of β-adrenergic receptor (βAR) all interact with G proteins as a central aspect of their signaling. The various βAR subtypes also associate differentially with a variety of other cytoplasmic and transmembrane proteins. These βAR-interacting proteins play distinct roles in the regulation of receptor signaling and trafficking. The specificity of βAR associations with various binding partners can help to explain key physiological differences between βAR subtypes. Moreover, the differential tissue expression patterns of many of the βAR-interacting proteins may contribute to tissue-specific regulation of βAR function.

Introduction

β-Adrenergic receptors (βARs) are G protein-coupled receptors (GPCRs) that mediate physiological responses to adrenaline and noradrenaline. These receptors are the molecular targets for some of the most commonly prescribed drugs in the history of medicine. βAR antagonists (“beta blockers”) are routinely used in the treatment of heart disease and hypertension, and β₂AR agonists, such as albuterol, are commonly used in the treatment of asthma. There are three receptor subtypes in this family: β₁AR is found at its highest levels in the heart and brain [1], β₂AR is more widely expressed [2], and β₃AR is found at its highest levels in adipose tissue [3]. All three receptors couple primarily to Gα_s to stimulate adenylyl cyclase, but can also couple to Gα_i in some cells under certain conditions [4], [5], [6].

The first proteins found to have functional interactions with βARs were, of course, G proteins [7]. Next was a kinase, originally called the β-adrenergic receptor kinase (βARK) [8] and now known as G protein-coupled receptor kinase 2 (GRK2). This kinase belongs to a family with seven closely related members, most of which are capable of associating with and phosphorylating β₁AR and β₂AR [9] but not β₃AR [10]. In a similar vein, β₁AR [11] and β₂AR [12], but not β₃AR [13], can be phosphorylated by protein kinase A (PKA), which can lead to feedback desensitization of βAR signaling, since activation of PKA is a downstream consequence of βAR-mediated adenylyl cyclase stimulation [14]. Finally, β-arrestins were identified as proteins involved in the desensitization of β₂AR [15], [16] and are also known to functionally interact with β₁AR [11] but not β₃AR [13] to regulate receptor internalization and desensitization in a manner that is dependent on GRK-mediated phosphorylation [17].

β₁AR and β₂AR share 54% sequence identity and are expressed in many of the same tissues. Furthermore, by the mid-1990s, the sets of cytoplasmic partners with which these two receptors were known to associate were exactly the same: Gα_s, GRKs, PKA, and β-arrestins (as described above). Paradoxically, however, physiological studies of the same era revealed that β₁AR and β₂AR could exert markedly different functional effects even when expressed in the same cell types. In cardiac myocytes, for example, β₁AR and β₂AR are expressed at similar levels and induce similar rises in cyclic AMP, yet exert quite different effects on the regulation of cellular calcium levels and contractility [18], [19], [20]. Furthermore, β₁AR and β₂AR also have opposing effects on the regulation of apoptosis in a variety of cell types [21], [22], [23], [24] and can differentially regulate calcium channel activity in adrenal chromaffin cells [25]. Studies with knockout mice have revealed significantly different phenotypes for β₁AR versus β₂AR knockouts [26], [27], further suggesting that the two receptors are capable of coupling to distinct intracellular signaling pathways.

The many differences observed between the effects of β₁AR and β₂AR on cellular physiology are inconsistent with the notion that the two receptors couple to precisely the same set of intracellular signaling proteins. Thus, over the past several years, a number of research groups have pursued studies aimed at elucidating novel βAR-binding partners. A special emphasis has been placed on finding proteins that interact differentially with β₁AR versus β₂AR and may therefore potentially contribute toward understanding the differential signaling and regulation of these two subtypes. This review will describe what is currently known about the subtype-specific interactions of βARs with various cytoplasmic proteins and will also summarize findings concerning βAR associations with transmembrane proteins, such as receptors and channels (Fig. 1, Fig. 2, Fig. 3, Fig. 4).