Introduction Not All 7tmrs Are Gpcrs

A common system of receptor activation in G protein-coupled receptors (GPCRs) has been contemplated often, primarily because of the conserved heptahelical structural motif and the shared signaling through G proteins. However, the great diversity in ligands has been used as a counter-argument against such considerations. The prevailing modern view is that no single "lock" exists for all agonist "keys" in GPCRs and that each ligand-receptor system has its own mechanistic binding and activation principle.1 Subsequent to ligand binding, it is presumed that ligand-induced conformational changes in the receptor are reasonably conserved for all receptors, allosterically regulating signal transduction intracellularly, and empowering the heterotrimeric G proteins and other effector mechanisms to modulate and interfere with cellular responses.

Not all 7TMRs are physiological receptors and transduce specific ligand signals, although all are pharmacological receptors, even if the only known ligands are simply the bound lipid molecules of the cell membranes. A distinction between binding ability (ligand-receptor binding) and bioactivity (ligand-induced, receptor-mediated biological activation) is also emphasized and confusing terms such as binding "activity" or "actives" are to be avoided. This regrettable terminology is commonly used to designate "hits" or "positives" in early stage drug discovery screening assays, and the assays are too often indirect assessments of binding inhibition by another marker ligand and thus afflicted by a preponderance of false positives. As a result, few descriptive terms are truly descriptive and many scientific misconceptions and bio(un)informatic analyses can be traced to misleading annotation.

Examples of the 7TMR sequence and topology superfamily are to be found in all biological kingdoms. Whereas the predominant signaling pathway is G protein activation and hence the GPCR designation, not all of the heptahelical membrane proteins which are considered parts of this structural or sequence-related superfamily actually couple to G proteins. The heptahelical protein and 7TMR designations acknowledge their structural ubiquity without the confusion of inappropriate attribution of a GPCR signal-transduction mechanism. A pharmacological definition of a 7TMR will be used throughout this chapter; the GPCR designation is usually retained for those receptors which signal via G proteins.

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