Dopamine receptor expression and function in the normal and pathological hypothalamus-pituitary-adrenal axis

Abstract

Dopamine is the predominant catecholamine neurotransmitter in the human central nervous system, where it controls a variety of functions including cognition, emotion, locomotor activity, food intake and endocrine regulation. Dopamine also plays multiple roles in the periphery as a modulator of cardiovascular and renal function, gastrointestinal motility and the endocrine system (1). Dopamine exerts its functions via the binding with dopamine receptors (1). Dopamine receptors belong to the family of seven transmembrane domain G protein-coupled receptors and include five different receptor subtypes, named D1-Ds. The members of dopamine receptor family are encoded by genes localized on different chromosome loci, displaying a considerable homology in their protein structure and function. The analysis of dopamine receptor structure and function suggests the existence of two different groups of receptors: D1-like, including D1 and D5 receptors, associated to a stimulatory function, and Dz-like, including Dz, D3 and D4 receptors, associated to an inhibitory function. The D1 and Ds receptors are encoded by intronless genes and share an 80% homology in their transmembrane domains. The Dz receptor shares a 75% homology with the D3 and a 53% homology with the D4 transmembrane domains and all three receptor subtypes are encoded by genes, which are interrupted by introns. The Dz receptor exists in two main variants, called Dzlong and Dzshort, generated by an alternative splicing of an 87 base pairs exon. These two D2 receptor isoforms differ for the presence or absence of a stretch of 29 amino acids in the third cytoplasmic loop in their protein structure. Splicing variants of the D3 receptor encoding nonfunctional proteins have been also identified. The analysis of the D4 receptor reveals the existence of polymorphic variations within the coding sequence, being a 48 base pairs sequence existent as a direct repeat sequence (D4.1), fourfold (D4.4), sevenfold (D4.7) or eleven fold (D4.11) repeat sequence. Therefore, the D4 receptor isoforms differ for the length of the third cytoplasmic loop and have one, four, seven or eleven times the same insert of a stretch of 19 amino acids in their protein structure. The Ds receptor has two related pseudogenes, which share a 95% homology with the gene and encode for truncated non functional forms of the receptor (1). The molecular characteristics of human dopamine receptor family are summarized in Table 1. A schematic representation of the human dopamine receptor is shown in Fig. 1.