[150th post!] GPCR receptor hidden life

hidden life of GPCR receptors unveiled with reporter approaches

Two recent studies exploited reporter genes to unveil hidden secrets of GPCR signaling which is apparently harder to die than expected. From the cell surface, G-Protein Coupled Receptors are activated by the intended ligand. According to the current feed-back dogma, excessive stimulation results in de-activation (de-sensitization) of the receptor and subsequent internalization.

• With a genetically-encoded FRET sensor, Païkan Marcaggi and colleagues noted on PNAS that prolonged exposure to a ligand (glutamate) actually increases the sensitivity of the receptor (mGluR) to its ligand, in marked contrast to the desensitization typically observed in such receptors. The group is prototyping a model for receptor activity in which mGluR1 signaling behavior relates primarily to overall duration of glutamate release rather than fluctuations in local neurotransmitter concentration.
• Following down the feed-back dogma, once internalized, GPCRs are supposed to stop signaling. Davide Calebiro and colleagues recently shared on PLOS Biology the results obtained with a transgenic mouse expressing a fluorescent sensor for GPCRs signaling. By analysing second messengers dynamics, they showed that a GPCR continues to stimulate second messenger production in a sustained manner after internalization.

By citing H.P. Rang,

Receptor theory is becoming increasingly inadequate as an overall framework for interpreting and analysing drug effects.

Studying reporter genes in the context of reporter mice might provide a revolutionary revision in neuroscience, endocrinology and pharmacology.

Marcaggi, P., Mutoh, H., Dimitrov, D., Beato, M., & Knopfel, T. (2009). Optical measurement of mGluR1 conformational changes reveals fast activation, slow deactivation, and sensitization Proceedings of the National Academy of Sciences, 106 (27), 11388-11393 DOI: 10.1073/pnas.0901290106

Calebiro, D., Nikolaev, V., Gagliani, M., de Filippis, T., Dees, C., Tacchetti, C., Persani, L., & Lohse, M. (2009). Persistent cAMP-Signals Triggered by Internalized G-Protein–Coupled Receptors PLoS Biology, 7 (8) DOI: 10.1371/journal.pbio.1000172