Naunyn-Schmiedeberg's Arch Pharmacol (1995) 352:1 10 © Springer-Verlag 1995 Martin C. Michel • Barry Kenny • Debra A. Schwinn Classification of l-adrenoceptor subtypes Received: 2 February 1995/Accepted: 23 February 1995 Abstract Two gl-adrenoceptor subtypes (~IA and ~IB) have been detected in various tissues by pharmacolo- gical techniques, and three distinct cDNAs encoding gl-adrenoceptor subtypes have been cloned. The pro- file of an increasing number of subtype-selective com- pounds at cloned and endogenous receptors recently has facilitated alignment between cloned and pharma- cologically defined gl-adrenoceptor subtypes. Thus, ~a-adrenoceptors (previously designated ~1¢), ~ib-ad- renoceptors and ~a-adrenoceptors (previously desig- nated ~la, ~la or ~la/d) are now recognized. Since the ~a-adrenoceptor shares characteristics with both ~A- and ~B-adrenoceptors, tissues previously reported to express glA- and/or ~iB-adrenoceptors may addition- ally contain ~a-adrenoceptors. This article reviews the features of all three subtypes and discusses possible pitfalls in their pharmacological identification. Key words CqA-Adrenoceptor • ~lB-Adrenoceptor - C~li)-Adrenoceptor • Nomenclature current concepts of ~l-adrenoceptor subtype classifica- tion have not always been straightforward and have generated considerable confusion within and even more outside the group of e~-adrenoceptor investiga- tors. More recent evidence, however, has allowed reso- lution of most of these problems. Therefore, we will describe the current concept of ~a-adrenoceptor sub- type classification and developments leading to this concept; additionally we will highlight problems which have occurred along the way and at least partly still persist. The discussion of such problems may also be helpful for investigators trying to classify other receptor families since many of these pitfalls do not appear to be specific for ~l-adrenoceptor subtypes. This article will mainly focus on data obtained by radioligand binding and recombinant DNA technology as they appear most powerful for receptor subtype classification. Functional aspects of cq-adrenoceptor heterogeneity have previously been reviewed elsewhere (Minneman 1988; Garcia-Sainz 1993; Ruffolo and Hieble 1994). Introduction et-Adrenoceptors mediate many of the physiological effects of the catecholamines adrenaline and norad- renaline. In recent years it has become clear that el- adrenoceptors are not a homogeneous entity but rather constitute a distinct subfamily within the overall family of adrenoceptors. The developments leadings to the M. C. Michel ( ~ ) Department of Medicine, Nephrology laboratory JG1, Klinikum, University of Essen, Hufelandstrasse 55, D-45122 Essen, Germany B. Kenny Department of Discovery Biology, Pfizer Central Research, Kent, UK D. A. Schwinn Departments of Anesthesiology, Pharmacology and Surgery, Duke University Medical Center, Durham, North Carolina, USA Historical aspects Heterogeneity of cq-adrenoceptors was originally sug- gested by Morrow and Creese (1986) on the basis of radioligand binding studies in rat brain. In these initial experiments they found that phentolamine and WB 4101 competed for [3HI prazosin binding with shallow and biphasic curves whereas prazosin, indoramine and dihydroergocryptine exhibited steep and monophasic competition curves; they designated the high and low affinity site for WB 4101 and phentolamine as C~IA- and elB-adrenoceptors 1, respectively. In 1987 Han et al. demonstrated that chloroethylclonidine (CEC) l In this paper we will refer to pharmacologically-defined tissue receptor subtypes by upper case subscripts (e.g. elA) and to cloned subtypes by lower case subscripts (e.g. ~la)