Sadee W, Hoeg E, Lucas J and Wang D Genetic Variations in Human G Protein-Coupled Receptors: Implications for Drug Therapy AAPS PharmSci 2001; 3 (3) article 22 (https://www.pharmsci.org/scientificjournals/pharmsci/journal/01_22.html).

Figures and Tables

Table 1. Sequence Variants of Human G Protein Coupled Receptors

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Figure 1.An example of the molecular G protein-coupled receptor architecture: proposed 7-transmembrane domain (TMD) topology of the human µ opioid receptor (MOR). The locations of the 7 TMDs are inferred from hydropathy analysis of the primary structure. The 3 extracellular and intracellular loops (e1-3 and i1-3) and the N- and C-terminal tails can vary considerably in length and sequence conservation among GPCRs.

Figure 2.Schematics showing the proposed interactions of calmodulin and G proteins with the i3 loop of the µ opioid receptor (MOR). Calmodulin is thought to block basal G protein coupling, but it is released upon receptor activation by an agonist such as morphine. Conversely, activation of G protein is thought to dissociate the G protein from the receptor, allowing calmodulin to gain access to the receptor. (Calmodulin may also bind to the Gb subunit.). After chronic morphine pretreatment, calmodulin is depleted from the plasma membrane, which appears to permit enhanced access of G proteins to the receptor and, paradoxically, increase basal G protein coupling after morphine pretreatment. Receptor phosphorylation at S268 (a CaM-kinase II consensus site) might play a role in regulating access of G proteins and calmodulin. The i3 loop of MOR contains a calmodulin-binding motif in its C terminal portion, consisting of a predicted amphipathic a-helix with several positively charged residues. Adapted from J Biol Chem. 1999;274:22081-22088; J Neurochem. 2000;75:763-771; J Neurochem. 2000;74:1418-1425.

Figure 3.Schematics of the periplasmic binding protein module in various proteins (adapted from AAPS PharmSci. 1999; https://www.pharmsci.org/scientificjournals/pharmsci/journal/venus/index.html ). The bacterial periplasmic binding proteins-serving as subunits of solute transporters and chemoreceptors-have fused with receptors and ion channels, providing the ligand-binding pocket. Several polymorphisms map to the PBP (periplasmic binding protein) module of G protein-coupled receptors (Table 1, calcium-sensing receptors).

Figure 4.Inactivating mutations of the V2 vasopressin receptor. Note the introduction of a termination codon at position 242 of the polypeptide, leading to a truncated receptor. Cotransfection of the missing C-terminus can restore receptor activity. Reproduced with permission from J Clin Endocrinol Metab. 1999;84:1483-1486.

Figure 5.Sequence variants of the b2 adrenergic receptor. Functional consequences are summarized in Table 1 . Q27E introduces resistance to agonist-induced down-regulation if present alone; however, it largely occurs in the same haplotype with R16G. The latter causes more rapid down-regulation and negates the sparing effect of Q27E (see Table 1 ).

Table 2. Haplotype Analysis of b2AR Gene

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Figure 6.Predicting clinical response to clozapine therapy of schizophrenic patients. Shown are the 6 polymorphisms used by Arranz et al⁴⁴ to predict response of individual patients with a 76% to 77% success rate. The predicted secondary structures of 5HT-2A and -2C are also shown as the presumed main targets of clozapine.

Figure 7.Selected polymorphisms of the µ-opioid receptor (MOR).

Figure 8.Schematics of the i3 loop of the µ-opioid receptor (MOR), showing the effects of mutations introduced by sit-directed mutagenesis or human polymorphisms (indicated by dark blue boxes) on G protein coupling and interaction with calmodulin. Basal signaling activity is reduced for R260H- and R265H-MOR, whereas calmodulin binding is reduced for R265H- and S268P-MOR (143-145,93a). Note that most variants with low calmodulin binding are located toward the C-terminal portion; however, the N-terminal portion of i3 also appears to play a role.