Significant Functional Differences Between Dopamine D Receptor Polymorphic Variants Upon Heteromerization with α Adrenoreceptors.

The functional role of the dopamine D receptor (DR) and its main polymorphic variants has become more evident with the demonstration of heteromers of DR that control the function of frontal cortico-striatal neurons. Those include heteromers with the α adrenoceptor (αR) and with the DR, localized in their cortical somato-dendritic region and striatal nerve terminals, respectively. By using biophysical and cell-signaling methods and heteromer-disrupting peptides in mammalian transfected cells and rat brain slice preparations, here we provide evidence for a new functionally relevant DR heteromer, the αR-DR heteromer, which is also preferentially localized in cortico-striatal glutamatergic terminals. Significant differences in allosteric modulations between heteromers of αR with the DR and DR polymorphic variants could be evidenced with the analysis of G protein-dependent and independent signaling. Similar negative allosteric modulations between αR and DR ligands could be demonstrated for both αR-DR and αR-DR heteromers on G protein-independent signaling, but only for αR-DR on G protein-dependent signaling. From these functional differences, it is proposed that the DR variant provides a gain of function of the αR-mediated noradrenergic stimulatory control of cortico-striatal glutamatergic neurotransmission, which could result in a decrease in the vulnerability for impulse control-related neuropsychiatric disorders and increase in the vulnerability for posttraumatic stress disorder.