Pharmacogenetics of Adrenergic Receptors

An understanding of GPCR pharmacogenetic variants, however, may be important in populations who are at risk to unusual drug reactions. One of the best examples of how pharmacogenetics has the potential to define personalized medicine has evolved from the study of adrenergic receptors. Mutated forms of GPCRs, such as adrenergic receptors, can elicit a wide spectrum of disease phenotypes or altered drug efficacies. Polymorphic adrenergic receptors have been reported to result in both gain and...

Regulators of G Protein Signaling

The RGS proteins are GAPs and are involved in the inactivation of the signal resulting from the coupling of GPCRs to high-affinity heterotrimeric G protein. G protein coupling depends on the hydrolysis of Ga-GTP to Ga-GDP. As shown in Fig. 6.2, the RGS proteins bind directly to activated Ga-GTP to serve as GAPs. These proteins limit the half-life of Ga-GTP by activating the Ga subunit's GTPase activity, thereby facilitating the termination of signaling (102-105). The RGS proteins exemplify the...

The Family of GRK Enzymes

The GRK family consists of seven well-characterized enzymes. These enzymes are distinguished by (1) the structural homology within the family (2) the specific amino acid sequences that a given GRK can phosphorylate (3) enzyme kinetics (169,181) and (4) GPCR disease phenotypes that are often manifested by dysregula-tion of GRK activity. Gain-of-function GPCR mutations are frequently found to be constitutively phosphorylated. Conversely, inadequate receptor desensitization and sequestration often...

Neurotransmitter Pharmacogenetics

Antipsychotic drugs bind to many GPCRs and other targets, such as neurotransmitter transporters. These GPCRs include dopaminergic, serotonergic, and muscarinic receptors. The genomic structure and expression of several of these genes is probably relevant to understanding disease progression and therapeutic outcome (3). 8.2.3.1 Dopamine Receptor Pharmacology Dopamine is a major catecholamine neurotransmitter in the central nervous system (37) that is involved in the neuroregulation of locomotor...

And Familial Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus (NDI) is characterized by renal tubular resistance to the antidiuretic effect of arginine vasopressin (AVP). NDI may be inherited as an autosomal dominant or X-linked recessive disorder. The autosomal dominant form of NDI results from mutations of the aquaporin 2 gene (AQP2). AQP2 encodes a water channel of the renal collecting duct. Its disruption causes autosomal dominant NDI (113,114) and occasionally recessive forms of the disease. The gene encoding the V2...

Asthma GPCR Pharmacogenomics

Studies of GPCRs in asthma can be differentiated on the basis of whether they measure the contribution of candidate genes to atopy, bronchial hyperreactivity (BHR), drug response nonresponse, or another phenotype. The contribution of selected GPCR variants to the risk for developing asthma or altered drug response is reviewed. The evidence suggests that the involvement of P2-adrenergic receptor (ADRB2) variants in the development of asthma and adrenergic drug pharmacogenetics (160). Although...