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It has long been appreciated that in response to the reduced cardiac output of the failing heart, the sympathetic nervous system (SNS) releases neurohormones to both stimulate the heart and retain salt and water. The postganglionic and systemic release of catecholamines stimulates guanine nucleotide (G) protein-coupled β-ARs of the myocardium, increasing heart rate, enhancing contraction, and improving cardiac performance. At the receptor level, agonist binding promotes dissociation of the heterotrimeric G protein into α and βγ subunits, stimulating adenylyl cyclase to increase cAMP production, and activating protein kinase A (PKA). Sustained -AR stimulation is deleterious over time, however, causing receptor desensitization and downregulation, loss of responsiveness to catecholamines, and further contractile dysfunction.
The harmful effects of chronic G protein-coupled receptor (GPCR) stimulation are initially mitigated by negative feedback via G protein-coupled receptor kinases (GRKs), originally called β-adrenergic receptor kinases. In a process termed homologous desensitization, GRKs phosphorylate agonist-bound receptors, leading to β-arrestin recruitment to the receptor. Consequently, dissociated G proteins are sterically inhibited from coupling to the receptor/β-arrestin complex and further downstream signaling is inhibited. Furthermore, β-arrestins target the receptor for clathrin-coated pits in the cell membrane that are internalized and either recycled back to the cell surface or degraded.
As changes in GRK expression have featured prominently in many cardiovascular pathologies, including hypertension, heart failure, myocardial infarction, and cardiac hypertrophy, GRKs have been intensively studied as potential diagnostic or therapeutic targets. Creative Biogene can offer a variety of GPCR related products including stable cell lines, viral particles and clones for your drug discovery projects in cardiovascular disease.
| ADGRB2 | ADGRB3 | ADORA2A | CCRL2 | CHRM2 | CHRM3 |
| CRHR1 | CXCR2 | CXCR3 | CXCR6 | CXCR7 | DRD3 |
| GPR1 | GPR65 | GPR84 | HTR6 | HTR7 | MRGPRX2 |
| NPFFR1 | NTSR1 | OXGR1 | PTGDR | PTGDR2 | PTGER1 |
| PTGER2 | PTGER3 | PTH1R | RXFP2 | SSTR1 | SSTR2 |
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