27 January 2007. Dopamine receptors come in five flavors (D1-D5), and until recently, they were regarded as five separate players, regulating adenylate cyclase signaling pathways in distinct ways. But the work of Susan George and colleagues at the University of Toronto, Ontario, Canada, cooks up a different recipe for dopamine receptor action.
Their newest paper, published online December 28, 2006, in PNAS, shows that hybrid oligomers of D1 and D2 dopamine receptors regulate calcium release and activation of the calmodulin-dependent kinase II α (CaMKIIα) in adult rat brain. Given the importance of this kinase in modulating synaptic plasticity, the results suggest that the novel D1/D2 partnership could help tune neuronal function in response to dopamine in adults. Understanding this wrinkle in dopamine action, and how it changes with age, may have some relevance for schizophrenia, drug abuse, and other disorders where dopamine signaling takes a central role (see SRF Current Hypothesis by Abi-Dargham).
Previously, George’s group has shown that the D1 and D2 receptors form hetero-oligomers in cells that have pharmacological and signaling properties distinct from either D1 or D2 alone (Lee et al., 2004; So et al., 2005). Rather than regulating adenylate cyclase, the combination receptor turns on phospholipase C, causing inositol phosphate production and internal calcium release.
In the new report, first author Asim Rashid leads the characterization of these hybrid receptors in the striatum in mouse brain. Just as in earlier cell-based experiments, the D1-D2 receptors were found to be coupled to phospholipase C activation via rapid stimulation of the Gq/11 signaling protein. The researchers show evidence that simultaneous activation of both D1 and D2 is required to see Gq/11 activation in membrane preparations from mouse striatum. Membranes from either D1 or D2 knockout mice did not support Gq/11 activation.
The pharmacology of the D2 receptor undergoes some changes when it meets up with D1, the researchers find. Two different agonists that are normally specific for D1 show binding to D2 when it is in the mixed complex. One feature of D2 that is not changed is the binding of the antipsychotic raclopride, which blocks the activation of Gq/11 by the mixed receptor.
Unexpectedly, the researchers found that the receptor complex is more abundant in adult mice (>8 months old) than in immature animals (3 months). Most studies on dopamine function use young rodents, which could explain the limited reports of functions for the D1-D2 receptors, the authors say.
In vivo studies demonstrate that the D1-D2 complex regulates calcium-dependent signals in adult rodents. Dosing rats with D1 and D2 agonists together resulted in activation of CaMKIIα in the nucleus accumbens, as measured by postmortem histochemistry. The activation required both D1 and D2, since either a D1 antagonist (SCH23390) or raclopride inhibited it, and neither D1 nor D2 knockout mice could support CaMKIIα activation.
Mixing and matching receptor subunits creates a novel dopaminergic signaling complex, which could play a role in schizophrenia, the authors conclude. The combinatorial receptor, they write, “is significant in that it provides a greater repertoire of signaling pathways by which dopamine can modulate neuronal function than would be possible by each of the five different dopamine receptor subtypes acting solely as separate units.” With both dopamine and calcium signaling implicated in schizophrenia, they conclude, their results provide “significant impetus to determine whether the D1-D2 receptor signaling complex is altered in neuropsychiatric decease.”—Pat McCaffrey.
Rashid AJ, So CH, Kong MM, Furtak T, El-Ghundi M, Cheng R, O'Dowd BF, George SR. D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum. Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):654-9. Epub 2006 Dec 28. Abstract