The dopamine D4 receptor: biochemical and signalling properties

Abstract

Dopamine is an important neurotransmitter that regulates several key functions in the brain, such as motor output, motivation and reward, learning and memory, and endocrine regulation. Dopamine does not mediate fast synaptic transmission, but rather modulates it by triggering slow-acting effects through the activation of dopamine receptors, which belong to the G-protein-coupled receptor superfamily. Besides activating different effectors through G-protein coupling, dopamine receptors also signal through interaction with a variety of proteins, collectively termed dopamine receptor-interacting proteins. We focus on the dopamine D4 receptor, which contains an important polymorphism in its third intracellular loop. This polymorphism has been the subject of numerous studies investigating links with several brain disorders, such as attention-deficit hyperactivity disorder and schizophrenia. We provide an overview of the structure, signalling properties and regulation of dopamine D4 receptors, and briefly discuss their physiological and pathophysiological role in the brain.

The Physiology, Signaling, and Pharmacology of Dopamine Receptors

“…The D2-class dopamine receptors (D2, D3, and D4) couple to the G␣ i/o family of G proteins and thus induce inhibition of AC. In contrast to the D1-class dopamine receptors, D2 and D3 dopamine receptors are expressed both postsynaptically on dopamine target cells and presynaptically on dopaminergic neurons (Sokoloff et al, 2006;Rankin et al, 2010;Rondou et al, 2010).…”

“…In general, different subtypes of dopamine receptors vary significantly in their sensitivity to dopamine agonists and antagonists (Missale et al, 1998;Sokoloff et al, 2006;Rankin et al, 2010;Rondou et al, 2010); for a detailed comparison of pharmacological properties of dopamine receptors, see the National Institute of Mental Health Psychoactive Drug Screening Program database (http://pdsp.med.unc.edu) or the International Union of Basic and Clinical Pharmacology database (http://www.iuphar-db.org). Over the past several decades, a number of selective compounds were developed for the D2, D3, and D4 dopamine receptor subtypes.…”

“…Although ligands that are generally selective for the D1 class (compared with their affinity for the D2 class) have been developed, the development of specific D5 dopamine receptor ligands has proven to be difficult. The maximal degree of selectivity has been achieved for the D4-selective antagonists, which show a selectivity of more than a 1000-fold compared with their affinity for the other subtypes, whereas compounds antagonizing the D3 dopamine receptor show a maximal selectivity of approximately 100-fold compared with their affinity for D2 dopamine receptors (Missale et al, 1998;Vallone et al, 2000;Seeman, 2006;Sokoloff et al, 2006;Rondou et al, 2010). The basic genetic and structural features of human dopamine receptors and a short list of their selective ligands are presented in Table 1.…”

Heteromeric Dopamine Receptor Signaling Complexes: Emerging Neurobiology and Disease Relevance

“…Although the distribution of the D1-D2 heteromer in PFC has not been characterized, approximately 15-25% of the pyramidal neurons in rodent medial PFC coexpress the D1R and D2R (Zhang et al, 2010), implicating these neurons in the antidepressant-like effects of D1-D2 heteromer disruption. ( Missale et al, 1998;Rondou et al, 2010). Unlike the rat D4R, the gene encoding the human D4R has a number of polymorphic variants (Van Tol et al, 1991), due to repeats of a 16 amino-acid sequence in the third intracellular loop, numbering between 2 and 11.…”

A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health

“…For example, several genetic studies have focused on the role of DA receptor dysfunction in human disorders. [13][14][15][16][17][18] However, as noted in 2000 by Wong and colleagues, 19 "while there are some evidences that polymorphisms and mutations in [DA] receptors can alter functional activity and pharmacological profiles, no conclusive data link these gene variants to drug response or disease." Unfortunately, this situation has not changed much over the past 10 years.…”