We have identified from human liver eight α1A-adrenoceptor (α1A-AR) splice variants that were also expressed in human heart, prostate and hippocampus. Three of these α1A-AR isoforms (α1A-1-AR, α1A-2a-AR and α1A-3a-AR) gave rise to receptors with seven transmembrane domains (7TMα1A-AR). The other five (α1A-2b-AR, α1A-2c-AR, α1A-3c-AR, α1A-5-AR and α1A-6-AR) led to truncated receptors lacking transmembrane domain VII (6TMα1A-AR). The 7TMα1A-AR isoforms transiently expressed in COS-7 cells bound [3H]prazosin with high affinity (Kd 0.2 nM) and mediated a noradrenaline (norepinephrine)-induced increase in cytoplasmic free Ca2+ concentration, whereas the 6TMα1A-AR isoforms were incapable of ligand binding and signal transduction. Immunocytochemical studies with N-terminal epitope-tagged α1A-AR isoforms showed that the 7TMα1A-AR isoforms were present both at the cell surface and in intracellular compartments, whereas the 6TMα1A-AR isoforms were exclusively localized within the cell. Interestingly, in co-transfected cells, each truncated α1A-AR isoform inhibited [3H]prazosin binding and cell-surface trafficking of the co-expressed ‘original’ 7TMα1A-1-AR. However, there was no modification of either the [3H]prazosin-binding affinity or the pharmacological properties of α1A-1-AR. Immunoblotting experiments revealed that co-expression of the α1A-1-AR with 6TMα1A-AR isoforms did not impair α1A-1-AR expression. Therefore the expression in human tissues of many truncated isoforms constitutes a new regulation pathway of biological properties of α1A-AR.
- receptor dimer
- regulation of G protein-coupled receptors
- The Biochemical Society, London © 1999