Heterodimerization of α2A- and β1-Adrenergic Receptors

Abstract

The physiological actions of epinephrine and norepinephrine are mediated via the activation of the following three distinct classes of G protein-coupled receptors (GPCR) 1 : ␣ 1 -, ␣ 2 -, and ␤-adrenergic receptors. Each class of adrenergic receptor (AR) is comprised of three closely related subtypes as follows: ␣ 1A -, ␣ 1B -, and ␣ 1D AR, which couple primarily to G q to stimulate phospholipase activity; ␣ 2A -, ␣ 2B -, and ␣ 2C AR, which couple primarily to G i to inhibit adenylyl cyclase activity; and ␤ 1 -, ␤ 2 -, and ␤ 3 AR, which couple primarily to G s to stimulate adenylyl cyclase activity (1). The adrenergic receptor subtypes are differentially distributed across various tissues, and tissue responses to epinephrine and norepinephrine are believed to be dependent upon the relative ratios of the various adrenergic receptors they express.Because ␤-and ␣ 2 -adrenergic receptors couple to G proteins with opposing actions on adenylyl cyclase activity, the two receptors might be expected to purely antagonize each other's signaling when they are co-stimulated in the same cell. However, it has been shown that ␣ 2 AR co-stimulation can in some cases paradoxically sensitize ␤-adrenergic signaling in brain tissue (2-4). Moreover, the pharmacological properties of ␤ARs in brain tissue are known to be regulated by ␣ 2 ARs (5, 6), and reciprocally the pharmacological properties of ␣ 2 ARs in brain tissue are known to regulated by ␤ARs (7,8). These examples of cross-talk and mutual regulation between ␤-and ␣ 2 -adrenergic receptors have been well known for more than 20 years, but the underlying molecular mechanisms remain unclear.GPCRs have traditionally been thought to exist as monomers, but recent studies (9) have revealed that they can exist in the plasma membrane as both homodimers and heterodimers. At present, a key question in this field is: how widespread is the phenomenon of receptor heterodimerization? The most clearcut case of the importance of GPCR heterodimerization comes from the GABA B receptor, a pharmacologically defined entity that is now known to be comprised of two distinct GPCRs, GABA B R1 and GABA B R2 (10). Because GABA B R1 and GAB-A B R2 are not functional when expressed by themselves, they represent a clear example of the physiological importance of receptor heterodimerization. Although other heptahelical receptors may not absolutely require heterodimerization to be functional in the same way that the GABA B receptor does, heterodimerization of other receptors may underlie some phenomena that are major question marks in our present understanding of neurotransmitter and hormone receptors, such as unexplained forms of cross-talk between different receptor subtypes.We wondered if the previously reported cross-talk between ␤ARs and ␣ 2 ARs in brain tissue might be due in part to a physical association between these two receptor types. Many early studies (11-13) of GPCR dimerization focused on the ␤ 2 AR. We have found recently (14) that the ␤ 1 AR also exhibits robust homodimerization in cells. Fu...

Cell-surface targeting of α2-adrenergic receptors — Inhibition by a transport deficient mutant through dimerization

“…This possibility is supported by a number of observations demonstrating that closely related members of G protein-coupled receptors may heterodimerize [11,14,[37][38][39]. Furthermore, α 2A -AR and α 2C -AR indeed form heterodimers with β 1 -AR and M 3 -muscarinc receptor, respectively [40,41]. As homo-and hetero-dimerization may play a crucial role in the regulation of cell-surface targeting, signaling specificity/efficiency and ligand binding selectivity of individual receptors [34], the finding that α 2B -AR exists in dimeric forms and possible heterodimerization between different α 2 -AR subtypes hints at the complexity of α 2 -AR and may open additional ways of understanding the function of this subfamily of G protein-coupled receptors.…”

“…Therefore, dimers are unable to export from the ER. Dimerization has been well described for a variety of G protein-coupled receptors [9][10][11][12][13][14][15][34][35][36][37][38][39][40][41]. However, whether α 2B -AR is capable of forming homodimers has not been reported.…”

Ligand-independent CXCR2 Dimerization

“…Cysteine residues in the fourth TM segment are responsible for D2 dopamine receptor dimerization (4), and disulfide bonds are also involved in the oligomerization of Ca 2ϩ (22), -opioid (13), sphingosine 1-phosphate (23), and V2 vasopressin receptors (18); sequences in the N-terminal extracellular domains are involved in mGluR (17) and CCR5 (24 -27) homodimer formation; the C-terminal region is essential for ␦-opioid receptor dimerization (12). The seventh TM domain controls noncovalent hydrophobic interactions for adrenergic receptors, which also require receptor glycosylation (7,8). Contrasting consequences are also reported for receptor functional properties: in some cases receptor dimerization is essential for receptor function, as demonstrated for GABA B (9 -11) and for the taste receptors (29); for other GPCRs, heterodimerization impairs or changes the features of their activation, as shown for the angiotensin II (6), the opioid and dopamine (30,31), and for the ␤-adrenergic receptors (32).…”

“…Receptor oligomerization has functional implications in terms of cell surface expression, ligand binding, signaling, and receptor trafficking (1). Many different GPCRs have been proved to undergo homoor heterodimer formation; these include the receptors for dopamine which can form both homo-(2-4) and heterodimers with somatostatin receptors (5), angiotensin A1 and A2 (6), adrenergic (7,8), GABA B (9 -11), ␦-and -opioid (12-15), rhodopsin (16), mGlu (17), vasopressin V2 (18), vasopressin/ossitocin (19), muscarinic (20), glucagon (21), Ca 2ϩ (22) sphingosine 1-phosphate (23), and the chemokine CXCR4, CCR2, and CCR5 receptors (24 -28). The molecular mechanism of receptor oligomerization varies among different receptors and involves transmembrane (TM) domains as well as extramembrane regions.…”

Regulation of α2AR trafficking and signaling by interacting proteins

“…Compared to the α 2A AR homodimerization, heterodimerization of the α 2A AR subtype with the α 2C AR subtype significantly attenuates agonist-induced phosphorylation of the α 2A AR subtype, leading to a reduction of arrestin binding as well as arrestin-mediated Akt activation by α 2 -agonist [16]. Heterodimerization of α 2A AR and β 1 AR in HEK cells significantly alters ligand binding properties of the β 1 AR but that of not the α 2A AR, and leads to internalization of β 1 AR in response to α 2 -agonists [17]. On the other hand, heterodimerization of α 2C AR with β 2 AR notably reduces the intracellular pool of α 2C AR in HEK cells, and such increased α 2C AR surface expression results in enhanced α 2C AR internalization and ERK activation in response to α 2 -agonist stimulation [18].…”