ABSTRACT
The ability of single agonists to interact with more than one second messenger system is now well established. Initially, this was thought to be mediated via an agonist interacting with a range of different G-protein coupled receptor subtypes (Bylund, 1992; Hosey, 1992), but recently the use of cloned receptors has shown that single receptor subtypes can be directly linked to multiple second messenger systems (Thompson, 1992). Thus the cloned muscarinic-M2 (Lai et al. 1991) and α2-adrenergic (Cotecchia et al. 1990) receptors both stimulate phosphoinositide hydrolysis and inhibit adenylate cyclase activity, whilst the cloned receptors for thyrotropin (Van Sande et al. 1990), calcitonin (Chabre et al. 1992), parathyroid hormone (Abou-Samra et al. 1992) and the three classes of tachykinin receptor (Nakajima et al. 1992; Mitsuhashi et al. 1992), all stimulate both pathways. The present paper reports that a cloned seven transmembrane spanning Drosophila octopamine/tyramine receptor (Arakawa et al. 1990; Sandou et al. 1990; Robb et al. 1991) permanently expressed in a Chinese Hamster Ovary K1 (CHO) cell line, both inhibits adenylate cyclase activity and leads to the elevation of intracellular Ca2+ levels by separate G-protein coupled pathways. However, tyramine is about two orders of magnitude more potent than octopamine, when assayed by direct binding or by depression of cyclic AMP levels, whereas octopamine is slightly more potent or faster than tyramine in causing a transient elevation of cytosolic Ca2+. Thus agonists of this cloned receptor, differing by only a single hydroxyl group in the side chain, may be capable of differentially coupling it to different second messenger systems. The phenomenon of agonist specific coupling of cloned receptors to different second messenger systems could alter our current concepts of receptor pharmacology.
