research
Dopamine receptor expression and function in the normal and pathological hypothalamus-pituitary-adrenal axis
- Publication date
- 1 January 2005
- Publisher
- __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.