Pathophysiological impact of the adhesion G protein-coupled receptor family.

G protein-coupled receptors (GPCRs) represent one of the most targeted drug classes in the human genome, accounting for greater than 40% of all Food and Drug Administration-approved drugs. However, the second-largest family of GPCRs, known as adhesion GPCRs (aGPCR), have yet to serve as a clinical target despite increasing evidence of their physiological and pathological functions, which suggests an opportunity toward the development of novel therapeutics. To date, the pathophysiological function of aGPCRs is associated with a plethora of diseases including cancer, central nervous system disorders, immunity and inflammation, and others. To highlight their potential as pharmacological targets, we will review three distinct aGPCR members (ADGRG1, ADGRE5, and ADGRF5), highlighting their molecular mechanisms of action and contributions to the development of pathophysiology.

Loss of cardiomyocyte-specific adhesion G-protein-coupled receptor G1 (ADGRG1/GPR56) promotes pressure overload-induced heart failure.

Adhesion G-protein-coupled receptors (AGPCRs), containing large N-terminal ligand-binding domains for environmental mechano-sensing, have been increasingly recognized to play important roles in numerous physiologic and pathologic processes. However, their impact on the heart, which undergoes dynamic mechanical alterations in healthy and failing states, remains understudied. ADGRG1 (formerly known as GPR56) is widely expressed, including in skeletal muscle where it was previously shown to mediate mechanical overload-induced muscle hypertrophy; thus, we hypothesized that it could impact the development of cardiac dysfunction and remodeling in response to pressure overload. In this study, we generated a cardiomyocyte (CM)-specific ADGRG1 knockout mouse model, which, although not initially displaying features of cardiac dysfunction, does develop increased systolic and diastolic LV volumes and internal diameters over time. Notably, when challenged with chronic pressure overload, CM-specific ADGRG1 deletion accelerates cardiac dysfunction, concurrent with blunted CM hypertrophy, enhanced cardiac inflammation and increased mortality, suggesting that ADGRG1 plays an important role in the early adaptation to chronic cardiac stress. Altogether, the present study provides an important proof-of-concept that targeting CM-expressed AGPCRs may offer a new avenue for regulating the development of heart failure.

Epidermal growth factor receptor association with ß1-adrenergic receptor is mediated via its juxtamembrane domain.

ß1-adrenergic receptor (ß1AR)-mediated transactivation of epidermal growth factor receptor (EGFR) engages downstream signaling events that impact numerous cellular processes including growth and survival. While association of these receptors has been shown to occur basally and be important for relaying transactivation-specific intracellular events, the mechanism by which they do so is unclear and elucidation of which would aid in understanding the consequence of disrupting their interaction. Using fluorescence resonance energy transfer (FRET) and immunoprecipitation (IP) analyses, we evaluated the impact of C-terminal truncations of EGFR on its ability to associate with ß1AR. While loss of the last 230 amino acid C-terminal phosphotyrosine-rich domain did not disrupt the ability of EGFR to associate with ß1AR, truncation of the entire intracellular domain of EGFR resulted in almost complete loss of its interaction with ß1AR, suggesting that either the kinase domain or juxtamembrane domain (JMD) may be required for this association. Treatment with the EGFR antagonist gefitinib did not prevent ß1AR-EGFR association, however, treatment with a palmitoylated peptide encoding the first 20 amino acids of the JMD domain (JMD-A) disrupted ß1AR-EGFR association over time and prevented ß1AR-mediated ERK1/2 phosphorylation, both in general and specifically in association with EGFR. Conversely, neither a mutated JMD-A peptide nor a palmitoylated peptide fragment consisting of the subsequent 18 amino acids of the JMD domain (JMD-B) were capable of doing so. Altogether, the proximal region of the JMD of EGFR is responsible for its association with ß1AR, and its disruption prevents ß1AR-mediated transactivation, thus providing a new tool to study the functional consequences of disrupting ß1AR-EGFR downstream signaling.