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

Abstract

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 D -like (D and D ), which activate adenylate cyclase, and the D -like (D , D and D ), 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 D -like and D -like DR are functionally active in human lymphocytes, although the D -like DR stimulation results in stronger effects in comparison to the D -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.

Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

“…Dopamine is produced in the peripheral and the central nervous system, and is generally associated with reward-motivated behavior in the brain. Lymphoid tissues can be innervated by dopaminergic neurons [ 173 ] and many types of immune cells (T and B lymphocytes, dendritic cells, monocytes/macrophages, neutrophils and natural killer cells), respond to dopamine via specific receptors expressed in both the innate and adaptive immune systems [ 174 ]. These receptors show distinct affinities for dopamine and, consequently, this neurotransmitter displays complex immunomodulatory roles, depending on its concentration, the receptor subtype and the target immune cell.…”

“…Central dopaminergic hypoactivity has been related to increased risk of inflammation [ 175 ]. For instance, dopaminergic inhibition of the immunosuppressive Treg function in response to endogenous or exogenous dopamine [ 176 ] was shown to occur through the activation of D 1 -like dopamine receptors that activate adenylate cyclase [ 177 ], hence favoring the uncontrolled proliferation of effector T cells [ 174 ]. Moreover, dopamine may differentially drive the differentiation of CD4 + T cells into Th1 or Th17 inflammatory phenotypes, depending on the context, and this could represent a driving force during autoimmunity [ 176 ].…”

Peripheral blood lymphocyte subpopulations in patients with bipolar disorder type II

“…Lymphocytes and macrophages have noradrenergic, cholinergic and peptidergic receptors on their surfaces which enables to create “neuroimmunological synapses” between nervous and immune cells 4 . Lymphocytes can bind different neurotransmitters including norepinephrine, dopamine, adrenaline, GABA, acetylcholine, and peptides (substance P, vasoactive intestinal peptide, somatostatin, neuropeptide Y) 4–6 . These substances control most of the functions of the immune cells such as differentiation, proliferation, antigen expression and cytokine production 4,6–8 .…”

Increased dopamine and its receptor dopamine receptor D1 promote tumor growth in human hepatocellular carcinoma

“…Emerging evidence has shown that activating the PI3K/AKT/CREB signaling pathway promotes cancer progression [31]. DRD1 accomplishes its function by increasing cAMP ( [32,33]). Our current research revealed that interfering with DRD1 expression effectively influenced HCC cell proliferation, migration, and invasion in vitro by targeting the cAMP/PI3K/AKT/CREB pathway.…”