Significant Functional Differences Between Dopamine D 4 Receptor Polymorphic Variants Upon Heteromerization with α 1A Adrenoreceptors.

The functional role of the dopamine D4 receptor (D4 R) and its main polymorphic variants has become more evident with the demonstration of heteromers of D4 R that control the function of frontal cortico-striatal neurons. Those include heteromers with the α2A adrenoceptor (α2A R) and with the D2 R, 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 D4 R heteromer, the α1A R-D4 R heteromer, which is also preferentially localized in cortico-striatal glutamatergic terminals. Significant differences in allosteric modulations between heteromers of α1A R with the D4.4 R and D4.7 R polymorphic variants could be evidenced with the analysis of G protein-dependent and independent signaling. Similar negative allosteric modulations between α1A R and D4 R ligands could be demonstrated for both α1A R-D4.4 R and α1A R-D4.7 R heteromers on G protein-independent signaling, but only for α1A R-D4.4 R on G protein-dependent signaling. From these functional differences, it is proposed that the D4.4 R variant provides a gain of function of the α1A R-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.