How is GPCR signaling regulated?

G-Protein Coupled Receptors (GPCRs) signaling is tightly regulated by a family of kinases (GRKs) which upon activation phosphorylate the receptor. This increases the affinity for the attachment of an arrestin, which prevents coupling of that receptor to its Ga-protein. This process is known as desensitization and occurs in response to agonist binding. If there is constant stimulation, it can create receptor internalization and down-regulation and weaken signaling. Desensitization may be adverse in conditions like heart failure when the desensitization of the B-adrenergic receptor leads to the decrease of ventricular generation. 

GRKs are a family of 7 members (GRK1-GRK7) which have similar structures (an N-terminus with an RGS domain, and a catalytic and a C-terminal domain. The GRK-1 subfamily (which consists of GRK1 and GRK7) are involved in rhodopsin mutations which are responsible for inherited retinal disorders. The GRK2 sub-family (which consists of GRK2 and GRK3) act on various GPCRs and play a role in causing diseases like heart failure. The GRK4 sub-family (which consist of GRK4, GRK5, and GRK6) specifically phosphorylate terminal amino acid residues. GRK4 has been identified to play a vital role in regulating the Dopamine D1 receptor, thus regulating blood pressure.