New insights into dopamine receptors in the central nervous system.

Whereas biochemical and pharmacological studies indicated that there were two subclasses of dopamine receptor (D1, D2) the application of molecular biology techniques has defined at least six dopamine receptor isoforms. These may be divided into D1-like (D1, D5) and D2-like (D2(short), D2(long), D3, D4) subfamilies on the basis of their structural and pharmacological properties. In this commentary the common properties of these dopamine receptor species are described, including the predicted structures of seven transmembrane alpha-helices, amino acid homologies and conserved amino acids that may play important structural and functional roles. The D1-like and D2-like receptor isoforms have individual properties and these are described in terms of their structures, pharmacological and biochemical properties and localizations in different brain regions. The existence of multiple dopamine receptor isoforms is important for understanding how certain drugs achieve their therapeutic effects and how unwanted side effects arise. This is considered for the anti-parkinsonian and anti-schizophrenic drugs. The localization of D1 and D2 dopamine receptors to particular cell types in the neostriatum allows new insights to be made into the normal mode of action of dopamine to control motor function and how this is disturbed in disease stages e.g. Parkinson's disease, Huntington's disease. The detailed mode of action of anti-parkinsonian drugs can also be better understood from this. The availability, from molecular biology studies, of the amino acid sequences of the receptor isoforms allows predictions to be made of the structures of these species. In particular it is possible to produce speculative models of the three dimensional structures of the ligand-binding sites of these receptors. These speculations can be complemented by chemical modification, pH dependency and mutagenesis studies which provide information on the amino acid residues at the ligand binding site that actually interact with the ligand. In time it should be possible to understand in some detail the mechanism of receptor-ligand interaction and this will be important for the design of drugs targeted at specific isoforms.