Presynaptic autoreceptors in the third decade: focus on α2‐adrenoceptors

Presynaptic autoreceptors were discovered by six groups of researchers in 1971. The receptors of 1971 were autoreceptors regulating the release of noradrenaline, acetylcholine and GABA (Starke et al. 1989). The ®rst 10 years after 1971 yielded the basic evidence. Carlsson (1975) coined the term `autoreceptors', receptors `sensitive to the neuron's own transmitter substance'. It was recognized that neurons may also possess autoreceptors in their soma-dendritic region. The second 10 years brought important pharmacological consequences: just like presynaptic a-autoreceptors had been the ®rst a2-adrenoceptors (Langer 1974), presynaptic serotonin autoreceptors now became the prototypical 5-HT1-receptors, presynaptic histamine autoreceptors the prototypical H3-receptors (Starke et al. 1989), and presynaptic glutamate autoreceptors activated by l-2-amino-4-phosphonobutyrate (l-AP4) became the prototypical metabotropic glutamate receptors (Monaghan et al. 1989). The second 10 years also witnessed a spirited denial of the function, and even the existence, of autoreceptors (Kalsner 1982; Starke 1987; Kalsner and Westfall 1990), an assault that, I believe, miscarried because the observations spoke, and speak, for themselves. The purpose of this article is to summarize events of the third decade of autoreceptor research, following our review of 1989 (Starke et al. 1989). Novel features comprised the further pharmacological classi®cation of the autoreceptors, their molecular identi®cation, their study by means of receptor-de®cient animals and a detailed elucidation of their signal transduction. These research steps of the third decade were common to presynaptic autoreceptors. However, instead of giving a general survey here, which would have to remain super®cial, I shall discuss one group of autoreceptors at some depth, the release-inhibiting a2-autoreceptors of noradrenergic neurones. They were the ®rst in which an inhibitory effect of the transmitter itself was demonstrated (Starke 1972). They are among the best-studied, and their study is representative of the study of other presynaptic autoreceptors. However, attention should be drawn to the fact that presynaptic glutamate autoreceptors, with ionotropic and metabotropic and with inhibitory and facilitatory members, were a focal point of interest in the last 10 years (MacDermott et al. 1999). a2-Autoreceptors: a2-adrenoceptor subclassi®cation Presynaptic a2-autoreceptors were not only the prototype a2-adrenoceptors (see above). Their study also showed ®rst that a2-adrenoceptors were not one single receptor type: they differed between rats and rabbits (Hieble et al. 1997). Radioligand binding experiments then indicated that there were four pharmacologically distinct a2-adrenoceptors, a2A, a2B, a2C and a2D (Bylund et al. 1994). On the basis of molecular genetic studies it is now generally accepted that many mammalian species including humans, rats, mice and guinea pigs possess three a2-adrenoceptor genes, of which one codes for the a2A/D-adrenoceptor, one for the a2B-adrenoceptor and one for the a2C-adrenoceptor. The designation a2A/D mirrors the fact that small differences in amino acid sequence lead to notable species differences in the pharmacological properties of this receptor, the receptor with a2A pharmacology (characterized for example by an antagonist af®nity ratio phentolamine ,, yohimbine, rauwolscine) occurring in humans and rabbits and the orthologous receptor with a2D pharmacology (characterized, for example, by an antagonist af®nity ratio phentolamine $ yohimbine, rauwolscine) in rodents. Part of the pharmacological difference can be attributed to a point mutation in the ®fth transmembrane domain of this receptor where cysteine in humans is replaced by serine in mice and rats (Link et al. 1992; Bylund et al. 1994; Hieble et al. 1997; Hein 2001).