cAMP levels in lymphocytes and CD4⁺ regulatory T-cell functions are affected by dopamine receptor gene polymorphisms

The neurotransmitter dopamine (DA) has prominent effects in the immune system and between the immune cells, CD4⁺ regulatory T (Treg) lymphocytes, a specialized T-cell subset crucial for the control of immune homeostasis, are especially sensitive to DA. Dopaminergic receptors (DR) are grouped into two families according to their pharmacological profile and main second messenger coupling: the D₁ -like (D₁ and D₅ ), which activate adenylate cyclase, and the D₂ -like (D₂ , D₃ and D₄ ), which inhibit adenylate cyclase and exist in several variants that have been associated to clinical conditions such as schizophrenia, bipolar disorder, substance abuse and addiction. We aimed to examine, in venous blood samples from healthy volunteers, the relationship between the arbitrary DR score and DR functional responses in human lymphocytes. All the samples were genotyped for selected DR gene variants (DRD1: rs4532 and rs686; DRD2: rs1800497 and rs6277; DRD3: rs6280; DRD4: rs747302 and seven 48-base pair variable number tandem repeat (VNTR)) and a DR score was attributed to each participant. We have also tested whether DR gene polymorphisms might affect Treg cell ability to suppress effector T-cell function. To our knowledge, this is the first study showing a correlation between DR gene variants and human T lymphocyte function. The main results are that both D₁ -like and D₂ -like DR are functionally active in human lymphocytes, although the D₁ -like DR stimulation results in stronger effects in comparison to the D₂ -like DR stimulation. In addition, it seems that the DR genetic profile may affect the ability of lymphocytes to respond to dopaminergic agents. More investigations are needed about the possible clinical relevance of such findings.