Proposed GPCR Activation Mechanisms

Biochemical and biophysical characterization of rhodopsin and the adrenergic receptors have identified residues near the cytoplasmic ends of TMIII and TMVI as important constraints on receptor structure and function. In the rhodopsin structure, the conserved E/DRYmotif found in TMIII is a central feature of the interface with TMVI. This structural motif in TMIII has been referred to as a functional microdomain because of its demonstrated functional significance in numerous GPCRs including the fi opiod receptor, 5-hydroxytryptamine2A receptor, ml muscarinic 

In rhodopsin, substitution of Glul34 (the E in E/DRY) with Gin enhances the basal activity of retinal-free opsin suggesting that the mutation causes the receptor to adopt a conformation that resembles the light activated wild type protein (Gohen et al., 1993). The acidic functional group of Glul34 is proposed to form a salt bridge with a primary amine 

Exactly how the cytoplasmic ends of TMIII and TMVI move away from one another remains difficult to pinpoint. As proposed by modeling 

This motif has been shown to be important in the activation of the 5-hydroxytryptamine2c receptor as well (Prioleau et al, 2002). The inter- 

---