Challenges in Evaluating Orphan GPCRs in the CNS

Receptor localization can provide the first clues to orphan GPCR function in normal and disease states, but it can be misleading in the brain. High throughput expression profiling is widely used to map orphan GPCR mRNA transcripts in the CNS, but receptor expression measured at the protein level often reveals different distributions because many receptors such as CB1 are localized to neuronal axon terminals distant from their origins of synthesis in cell bodies.201

Receptor distribution can also differ significantly across species. A number of CNS GPCRs recently deorphanized, including the trace amine receptors202 and the sensory neuron-specific receptors (SNSRs),203 differ in the number of alleles for highly homologous receptor subtypes in rodents and humans, making alignment of species homologs very difficult. Knockout mice have been used widely to gain insight into the functions of orphan GPCRs, but this has met with mixed success for CNS receptors because of compensatory mechanisms and confounding behavioral consequences of gene deletions.

Advances in RNAi technology and development of receptor-selective ligands may allow the study of receptor functions in challenging neurochemical and behavioral assays.200 Overall, the process of evaluating orphan GPCR function is still guided by a combination of convenience, serendipity, and intuition. Orphan receptors are described in more detail in Chapter 16.

0 0

Post a comment