Received for publication May 23, 2008.
Revised May 29, 2008.
Accepted for publication May 29, 2008.

Protein-Protein Interactions and Dopamine D2 Receptor Signaling: a Calcium Connection (Relates to article by Liu, et al., FastForward 29 April 2008)

Abstract

The third cytoplasmic loop is a crucial site of physical contact between some G protein-coupled receptors (GPCRs) and their respective G proteins. However, interactions occur not just between these proteins, but also involve a number of additional protein binding partners. It is thought that modulation of these protein-protein interactions may represent an important new avenue of pharmacotherapy through which signaling of GPCRs can be modulated. In the current issue of Molecular Pharmacology, Liu et al. (p XXXX) report that dopamine D2 receptors interact with the Ca2+ binding protein S100B. Using the third intracellular loop of the dopamine D2 receptor as bait in a bacterial two-hybrid system, S100B was determined to be a potential binding partner. They used pull-down assays both in vitro and in vivo to confirm the interaction and define its specificity. Neither the D3 nor D4 receptor expresses the motif conferring the interaction, and peptides based on the third intracellular loop of the D3 receptor did not pull down S100B. Some groups might stop there, but Liu and colleagues moved on to demonstrate co-localization of the D2 receptor and S100B by immunostaining. Functional assays were then used to show that co-expression of S100B with the D2 receptor increases the ability of D2 receptors to activate ERK and to inhibit adenylyl cyclase. These data suggest that S100B co-expression may serve as an important mediator of D2 receptor signaling efficacy in the brain. These interactions contribute to cellular, regional, and developmental differences in D2 receptor activation.

Key words: Dopamine, Gi family, Calcium (G Protein Coupled Signals)