7TM receptors

G-proteins, trim eric membrane-bound proteins that have intrinsic GTPase activity and act as intermediaries between 7TM receptors and a host of cellular effectors see Section 2.2. 

The human oxytocin receptor gene was isolated and characterised in 1994 [122], heralding the development of modern cloned receptor screening. The oxytocin receptor belongs to the Family A series of G-protein coupled 7-transmembrane receptors (GPCRs). A schematic representation of the generic structure of 7TM receptors is shown in Figure 7.3. 

Rhodopsin-Like 7TM Receptors Are the Quantitatively Dominant Family.88... 

Family B Is a Distinct Family of Glucagon/VIP/Caldtonin 7TM Receptors.91... 

TM Receptors Are in a Dynamic Equilibrium between Active and Inactive... 

TM Receptors Have Multiple Agonist Binding Modes.99... 

TM Receptors Appear to Function in Protein Complexes Together with Other... 

TM Receptors Are Phosphorylated by Both Second-Messenger Kinases... 

A Multitude of Very Different Chemical Messengers Act through 7TM Receptors... 

FIGURE 2.1 A side view of the structure of the prototype G-protein-coupled, 7TM receptor rhodopsin. The x-ray structure of bovine rhodopsin is shown with horizontal gray lines, indicating the limits of the cellular lipid membrane. The retinal ligand is shown in a space-filling model as the cloud in the middle of the structure. The seven transmembrane (7TM) helices are shown in solid ribbon form. Note that TM-III is rather tilted (see TM-III at the extracellular and intracellular end of the helix) and that kinks are present in several of the other helices, such as TM-V (to the left), TM-VI (in front of the retinal), and TM-VII. In all of these cases, these kinks are due to the presence of a well-conserved proline residue, which creates a weak point in the helical structure. These kinks are believed to be of functional importance in the activation mechanism for 7TM receptors in general. Also note the amphipathic helix-VIII which is located parallel to the membrane at the membrane interface. 

FIGURE 2.3 The three main families of mammalian G-protein-coupled 7TM receptors in mammals. No obvious sequence identity is found between the rhodopsin-like family A, the glucagon/VIP/calcitonin family B, and the metabotropic glutamate/chemosensor family C of G-protein-coupled 7TM receptors, with the exception of the disulfide bridge between the top of TM-III and the middle of extracellular loop-2 (see Figure 2.2). Similarly, no apparent sequence identity exists among members of these three families and, for example the 7TM bitter taste receptors, the V1R pheromone receptors, and the 7TM frizzled proteins, which all are either known or believed to be G-protein-coupled receptors. Bacteriorhodopsins, which are not G-protein-coupled proteins but proton pumps, are totally different in respect to amino-acid sequence but have a seven-helical bundle arranged rather similarly to that for the G-protein-coupled receptors. 

RHODOPSIN-LIKE 7TM RECEPTORS ARE THE QUANTITATIVELY DOMINANT FAMILY... 

One of the most highly conserved features among 7TM receptors is the disulfide bridge between the Cys at the top of TM-III and a Cys situated somewhere in the middle of the second extracellular loop. This loop is thereby transformed into two loops connecting the top of TM-III with the top... 

Much biochemical evidence shows that many if not all 7TM receptors have a strong tendency to aggregate both with themselves and with other 7TM receptors, as most clearly seen in multiple high-molecular-weight bands on sodium dodecyl sulfate (SDS) gels. These bands are by no means restricted to dimers as, in most cases, several higher order oligomeric structures are observed. This is an important point to consider when the functional correlation of dimer formation is addressed in non-family C receptors. 

The GABAb receptor is not a single 7TM receptor but rather a heterodimer formed by two 7TM receptors from family C. The GABAb-R1 receptor, which was initially cloned, binds the ligand GABA, but when expressed alone it is to a large extent retained in the endoplasmic reticulum,... 

TM RECEPTORS ARE IN A DYNAMIC EQUILIBRIUM BETWEEN ACTIVE AND INACTIVE CONFORMATIONS... 

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