Dimerization of α1-adrenoceptors

Three distinct genes encode α1-adrenoceptors. Although homodimers of each subtype have been reported, certain but not all combinations of heterodimers of the α1-adrenoceptors appear to form. Key studies in this field are reviewed and the approaches that have been applied to monitoring the selectivity and the basis of α1-adrenoceptor dimerization are discussed. Introduction GPCRs (G-protein-coupled receptors) are encoded by one of the largest gene families in the human genome. In the region of 400 genes encode GPCRs that respond to endogenously produced ligands and some 350 others encode GPCRs that respond to exogenous ligands, including odorants and tastes. In the recent past, it has become increasingly clear that GPCRs can exist as dimers or higher-order oligomers and that this may be integral to their function [1–3]. The rhodopsin-like or class A GPCRs are by far the largest family with the metabotropic glutamate receptor-like, class C receptors being the smallest. Despite the small number of class C GPCRs, studies on their expression and function have been integral to appreciation of the importance of dimerization for function. For example, although cloning of a seven-transmembrane polypeptide, class C GPCR that bound a high-affinity GABAB (γ -aminobutyric acid B) receptor antagonist seemed initially to identify this receptor [4], it was soon apparent that this polypeptide was not effectively transported to the surface of transfected cells. Furthermore, response of this receptor to GABA was either poor or non-existent. The recognition that co-expression of a second, highly homologous GPCR, the GABAB r2, was required to allow effective cell-surface delivery and function of the original polypeptide, now known as the GABAB r1, helped to define the functional GABAB receptor as an obligate heterodimer [5–7]. Although a special case, in that only the GABAB r1 is capable of binding GABA and hence initiating a signal, the requirement for the GABAB r2 to allow effective G-protein coupling [8] provided an intellectual framework for related studies on homodimers and heterodimers of other GPCRs. Equally, taste cells that express one or pair-wise combinations of three class C GPCRs, T1R1, T1R2 and T1R3, allow the detection of sugars and amino acids that are mainly associated with positive taste sensations. Sweet and umami (the taste of monosodium glutamate) are the main attractive taste modalities in man. Although there are means to detect sweet and umami