Signal Switching, Crosstalk, and Arrestin Scaffolds

Abstract

H ormone agonists, including angiotensin II (Ang II), norepinephrine, urotensin II, endothelin-1, vasopressin, and serotonin, mediate a plethora of physiological and pathological cardiovascular events via their cognate 7 membrane-spanning G protein-coupled receptors (GPCRs). On ligand binding, GPCRs undergo conformational changes that enable the activation and dissociation of heterotrimeric guanine nucleotide binding proteins (G proteins) and trigger a range of intracellular second messenger signaling cascades. Because of the immediacy of second messenger generation, GPCRs are able to acutely regulate cardiovascular events such as heart rate, contractile force, and systemic vascular resistance. Compelling evidence for GPCR control in the vasculature comes from both transgenic studies and clinical findings. For example, ␤-adrenergic receptor blockers and inhibitors of the synthesis and binding of Ang II are proven antihypertensive therapeutics for humans. Furthermore, mice lacking RGS2, a regulatory protein that enhances the speed of GPCR signal termination, display marked hypertension, increased basal vascular tone, and hypersensitivity to vasoconstrictive agonists, 1 a phenotype that demonstrates the contribution of immediate GPCR-dependent signals, as well as the effect of GPCR dysregulation on cardiovascular homeostasis.The evidence that signals emanating from GPCRs also contribute to the chronic development of vascular disease is persuasive. Overexpression of the G␣q subunit in cardiomyocytes directly stimulates cardiac hypertrophy and decompensated heart failure, 2 whereas transgenic mice expressing an inhibitory fragment of G␣q exhibit reduced hypertrophy in response to pressure overload. 3 GPCR agonists like Ang II, endothelin-1, and norepinephrine, act directly on cardiomyocytes to stimulate hypertrophy. 4 Meanwhile, Ang II contributes to atherosclerosis via activation of vascular smooth muscle cell (VSMC) migration and hypertrophy; this occurs either directly, via the Ang II type 1 receptor (AT 1 R), or indirectly by stimulating endothelin-1 expression or activating inflammatory pathways. 5 Importantly, these pathological vascular effects require significant modulation of gene transcription, often via activation of growth-promoting mitogen-activated protein kinase (MAPK) cascades.A confounding issue in GPCR biology has been the incongruity between acute second messenger signals generated by ligand binding and longer-term changes in gene expression and cell growth. Indeed, studies over the past decade have demonstrated that GPCR signaling is more complicated than predicted by the ternary complex model of receptor-G protein-effector signaling. Receptor coupling specificity can be modified by phosphorylation, not only quantitatively in terms of desensitization, but also qualitatively via G protein "switching." Many, if not most, GPCRs engage in crosstalk with receptor tyrosine kinases (RTKs). Transactivation of epidermal growth factor (EGF) receptors allows GPCRs to initiate Ras-dependent signals that cont...

Switching of G-protein Usage by the Calcium-sensing Receptor Reverses Its Effect on Parathyroid Hormone-related Protein Secretion in Normal Versus Malignant Breast Cells

“…As a result of this switch in G-protein usage, downstream signaling transitions from cAMP/PKA pathways to MAPK activation. G-protein switching has been noted for the ␤2-adrenergic receptor both in vitro and in vivo and has been suggested to contribute to the development of cardiac hypertrophy in states of chronic catecholamine excess (61,62). Recent data have also demonstrated that association of the ␤2-adrenergic receptor with ␤-arrestin can modulate the magnitude of G-protein switching (63).…”

“…Dynamic feedback switching from G␣ s to G␣ i usage has been documented to occur in response to ligand binding for several receptors, including the ␤1-and ␤2-adrenergic receptors, the prostacyclin receptor, and the vasoactive intestinal polypeptide receptor (45,(57)(58)(59). This particular phenomenon of G-protein switching has been most intensively studied for the ␤2-adrenergic receptor (57,60,61). Binding of ligand to this receptor leads to activation of G␣ s , generation of cAMP, and PKA-mediated phosphorylation of sites within the third intracellular loop and C-terminal tail of the receptor (57).…”

Designing Heart Performance by Gene Transfer

“…While the highest proportion of ␤-ARs in the heart are ␤ 1 -receptors, the proportion of ␤ 2 -receptors increases with heart failure, as ␤ 1 -ARs are downregulated during chronic stimulation (754,828,1010). Adenoviral gene transfer of two different naturally occurring ␤ 1 -AR polymorphisms to isolated rodent cardiac myocytes had significant chronotropic effects, and one of the ␤ 1 -AR variants greatly enhanced the sensitivity of the myocytes to a common ␤-blocker used to treat heart failure (751).…”

“…␤ 2 -ARs signal via multiple downstream pathways. Gene transfer of ␤ 1 -AR or ␤ 2 -AR into double knockout mice indicated that the protective effects of ␤ 2 -AR are likely mediated via G␣ i and the downstream activation of phosphoinositide 3-kinase (PI3K) and Akt (477,1015) or via functionally discrete signaling pools (506,828).…”

A Single Initiating Cause of Hypertension; Potential for Primary Prevention

“…In case of AT1r, the transactivation of EGFR and stimulation of MAPK is brought about by a variety of mediators [55,59], independently of a specific agonist. The same is true of AT2r and the production of nitric oxide, the essential end mediator of its effects, does not always require the selective agonist angiotensin II [60].…”