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

The functional role of the dopamine D 4 receptor (D 4 R) and its main polymorphic variants has become more evident with the demonstration of heteromers of D 4 R that control the function of frontal cortico-striatal neurons. Those include heteromers with the α 2A adrenoceptor (α 2A R) and with the D 2 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 D 4 R heteromer, the α 1A R-D 4 R heteromer, which is also preferentially localized in cortico-striatal glutamatergic terminals. Significant differences in allosteric modulations between heteromers of α 1A R with the D 4.4 R and D 4.7 R polymorphic variants could be evidenced with the analysis of G protein-dependent and independent signaling. Similar negative allosteric modulations between α 1A R and D 4 R ligands could be demonstrated for both α 1A R-D 4.4 R and α 1A R-D 4.7 R heteromers on G protein-independent signaling, but only for α 1A R-D 4.4 R on G protein-dependent signaling. From these functional differences, it is proposed that the D 4.4 R variant provides a gain of function of the α 1A 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.