Alpha-adrenoceptor subtypes

Different studies have led to our present knowledge of the membrane receptors responsible for mediating the responses to the endogenous catecholamines. These receptors were initially differentiated into alpha- and beta -adrenoceptors. alpha -Adrenoceptors mediate most excitatory functions, and were in turn differentiated in the 1970s into alpha (1)- and alpha (2)-adrenoceptors. The alpha (1)-adrenoceptor type usually mediates responses in the effector organ. The alpha (2)-adrenoceptor type is located presynaptically and regulates the release of the neurotransmitter but it is also present in postsynaptical locations. Both alpha -adrenoceptors are important for the control of vascular tone, but we now know that neither alpha (1)- nor alpha (2)-adrenoceptors constitute homogeneous groups. Each alpha -adrenoceptor type can be subdivided into different subtypes and in this review we have turned our attention to these. The alpha (1)- and the alpha (2)-adrenoceptor subtypes were previously defined pharmacologically by functional and binding studies, and later they were also isolated and identified using cloning methods. In fact, the study of alpha -adrenoceptors was revolutionized by the techniques of molecular biology which permitted us to establish the present classification. The present classification of alpha (1)-adrenoceptors stands as follows: alpha (1A)-adrenoceptor subtype (cloned alpha (1c) and redesignated alpha (1a/c)), alpha (1B)-adrenoceptor subtype (cloned alpha (1b)) and alpha (1D)-adrenoceptor subtype (cloned alpha (1d) and redesignated alpha (1a/d)). It has not been easy to establish the distribution of these alpha (1)-adrenoceptor subtypes in the various organs and tissues, or to define the functional response mediated by each one in the different species studied. Nevertheless it seems that the alpha (1A)-adrenoceptor subtype is more implicated in the maintenance of vascular basal tone and of arterial blood pressure in conscious animals, and the alpha (1B)-adrenoceptor subtype participates more in responses to exogenous agonists. It has also been observed that the expression of the alpha (1B)-adrenoceptor subtype can be modified in pathological situations and particular attention has been paid to the regulation of expression of this receptor. The present classification Of alpha (2)-adrenoceptors stands as follows: alpha (2A/D)-adrenoceptor subtype (today it is accepted that the alpha (2A)-adrenoceptor subtype and the alpha (2D)-adrenoceptor subtype are the same receptor but they were identified in different species: the alpha (2A) in human and the alpha (2D) in rat); alpha (2B)-adrenoceptor subtype (cloned alpha (2b)) and alpha (2C)-adrenoceptor subtype (cloned alpha (2c)). Today we know that the alpha (2A/D-) and alpha (2B)-adrenoceptor subtypes in particular control arterial contraction, and that the alpha (2C)-adrenoceptor subtype is responsible above all for venous vasoconstriction. We also know that the alpha (2A/D)-adrenoceptor subtype fundamentally mediates the central effects of the alpha (2)-adrenoceptor agonists. Despite the validity of the above-mentioned classification of the alpha (1)- and alpha (2)-adrenoceptors, it seems clear that the contractions of a large number of tissues including smooth muscle are mediated by more than one alpha -adrenoceptor subtype. Moreover, few ligands recognise only one alpha -adrenoceptor subtype and the lack of specifity in the different drugs for each one limits their administration in vivo and their therapeutic use, (C) 2001 Academic Press.