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.