Neuronal Cell Environment

Neuronal cell environments are highly differentiated and exert strong influences on GPCR function. The study of ligand-receptor interactions in a system that closely mimics the native environment of the receptor in vivo represents an ongoing challenge. Overexpression of GPCRs in recombinant systems can exaggerate agonist efficacy of ligands such that compounds with partial agonist activity in vivo appear to be full agonists. Therefore, the true differentiation of full and partial agonism must be determined in vivo.

Constitutive activity of GPCRs and subsequently the ability of ligands to demonstrate inverse agonism (i.e., decreased basal receptor activity in the absence of an agonist) is also heavily cell context-specific. Apparent constitutive activity is often seen for heterologously expressed GPCRs and has been demonstrated in vivo,89 suggesting that inverse agonists will have therapeutic profiles different from those of antagonists.

Although traditionally thought to function as monomeric units, mounting evidence indicates that GPCRs function as oligomers and that pharmacological pheno-

types of hetero-oligomers may differ from those of homo-oligomers (see Chapter 15, this volume).10

In fact, GPCRs themselves can function as cell-specific accessory proteins, as seen with the GABA-B receptor.11 As shown in Table 7.1, most of the known GPCR families in the CNS contain multiple receptor types, with significantly overlapping expression patterns in the six key CNS regions shown, both within and between GPCR families. Thus, a wide range of hetero-oligomers may be possible in the CNS, providing much greater diversity in functional receptor units than is possible through receptor variants alone.67

Additional non-GPCR proteins may also alter receptor specificity or signaling directly or indirectly.68 The nature and physiological relevance of receptor interactions are outside the scope of this chapter, but it is recognized that our understanding of drug effects and activities of endogenous ligands will be expanded in the coming decade to include the functional diversity of protein complexes.

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