Are there more than two types of alpha-adrenoceptors involved in physiological responses?
The application of the four main techniques available for examining the properties of alpha-adrenoceptors, gene coding, radioligand, biochemical and functional methods, has reinforced the earlier subclassification (alpha 1- and alpha 2-subtypes). These different techniques have not yet yielded subclassifications which entirely align when the subtypes have been examined in detail, although a prime reason for this is that the different techniques have not yet all been applied to the same receptors. There is evidence available on each level to indicate that there are further subtypes within the alpha 1- and alpha 2-adrenoceptors as originally defined pharmacologically, with the possible exception of functional evidence at cellular and tissue level for subtypes of alpha 2. The present extension of the subclasses to three each (A,B,C) for alpha 1 and alpha 2 does not withstand cross-examination on every level and seems unlikely to withstand further probing. It remains true that the set of subtypes of alpha-adrenoceptor which can be activated or blocked by drugs in functioning intact tissue preparations and which are shown in Fig. 4 has not been added to by knowledge derived from ligand binding or molecular biology. These techniques have bolstered confidence in the existing functioning categories and have enabled acceleration of drug screening programmes to find new, potent, highly selective antagonists for the known receptors. Rather than taking the categorization of receptors away from the recognition site to the larger molecule, they have reinforced its supremacy. The advantages being gained from the molecular biology of receptors lie in understanding cell signalling and, on the wider genetic scale, on the place of the receptors, among other elements of the cell, in regulation and function within the organism. From the physiologist's point of view, classical pharmacology can still be relied on as the basis for understanding the specificity of drugs which activate or block plasmalemmal receptors and to keep the numbers of these receptors within reason, while molecular biology may increasingly provide the tools to study the subsequent physiological events. A few years ago, one of us commented (in jest!) that the availability of so many different techniques for examining the properties of alpha-adrenoceptors may eventually provide the ultimate answer that there are forty-two subtypes, but that along the way, the original reason for requiring classification might become lost (McGrath, 1983 b).(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Physiology and Pharmacology, Medical School, Nottingham.
V G
VG
Wilson
C M
CM
Brown
J C
JC
McGrath
D000316:Adrenergic alpha-Agonists / Q000378:metabolism; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D015870:Gene Expression; D006801:Humans; D011942:Receptors, Adrenergic, alpha / Q000145:classification / Q000235:genetics / Q000502:physiology*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D011942:Receptors, Adrenergic, alpha