α-Adrenoceptors

Abstract

Major advances have been made in our understanding of the molecular structure and function of the alpha-adrenoceptors. Many new subtypes of the alpha-adrenoceptor have been identified recently through biochemical and pharmacological techniques and several of these receptors have been cloned and expressed in a variety of vector systems. Currently, at least seven subtypes of the alpha-adrenoceptor have been identified and the molecular structure and biochemical functions of these subtypes are beginning to be understood. The alpha-adrenoceptors belong to the super family of receptors that are coupled to guanine nucleotide regulatory proteins (G-proteins). A variety of G-proteins are involved in the coupling of the various alpha-adrenoceptor subtypes to intracellular second messenger systems, which ultimately produce the end-organ response. The mechanisms by which the alpha-adrenoceptor subtypes recognize different G-proteins, as well as the molecular interactions between receptors and G-proteins, are the topics of current research. Furthermore, the physiological and pathophysiological role that alpha-adrenoceptors play in homeostasis and in a variety of disease states is also being elucidated. These major advances made in alpha-adrenoceptor classification, molecular structure, physiologic function, second messenger systems and therapeutic relevance are the subject of this review.

Effects of modulatory agents on neurally-mediated responses of trout intestinal smooth musclein vitro

“…Stimulation of EP 3 and c%-receptors both induce negative feedback of neurotransmitter release from nerve endings with resultant decrease in cyclic AMP and reduced activity of neuronal calcium channels (Lefkowitz et al 1990;Coleman et al 1994;Ruffolo and Hieble 1994). Moreover, our studies have indicated that the specific t~2-agonist, guanabenz, also has some inhibitory activity on the contractile effects of 5-HT on trout intestine.…”

“…Receptor heterogeneity as a consequence of the species being used may offer an explanation for the lack of effect of idazoxam: We have previously shown that inhibition by classical antagonists of serotoninergic and muscarinic contractions of rainbow trout intestine is non-competitive (Burka et al 1989), in comparison to competitive antagonism observed in mammalian intestine. At present, there are at least three different types of t~2-adrenoceptors and there is considerable evidence that there are differences in t~2-adrenoceptors between species (Ruffolo and Hieble 1994;Watson and Girdlestone 1995). Idiosyncracies in ~2-adrenoceptor agonists have previously been reported in experiments on rainbow trout stomach (Kitazawa et al 1988).…”

“…The inhibition of transmurally stimulated contractions by forskolin could be due to either to inhibition of neurotransmitter release or functional antagonism of the neurotransmitters on smooth muscle contraction. The latter is the more likely situation because increases in neuronal cyclic AMP levels have been associated with closure of K + channels resulting in increased neurotransmitter release (see Darnell et al 1990) and agents which induce negative feedback of neurotransmitter release, such as ot2-agonists and PGE2, decrease intracellular levels of cyclic AMP (Coleman et al 1994;Ruffolo and Hieble 1994). The ability of substance P to contract the rainbow trout intestine confirms the presence of tachykinin receptors sensitive to substance P (Jensen and Holmgren 1991).…”

“…Stimulation of %-receptors results in hyperpolarization and relaxation of mammalian intestinal smooth muscle and stimulation of prejunctional ~x2-receptors will result in decreased release of the contractile neurotransmitters, acetylcholine and 5-HT, possibly by an inhibition of neuronal calcium channels (Lefkowitz et al 1990;Ruffolo and Hieble 1994). Stimulation of prejunctional c~2-receptors has also been linked to decreases m intracellular cyclic AMP levels (Lefkowitz et al 1990;Ruffolo and Hieble 1994), although the physiological implication of this phenomenon is not apparent. Postjunctional %-receptors also occur in smooth muscle, but their physiological function is not well understood (Timmermans and Van Zwieten 1981).…”

Glucose-induced sympathetic activity and energy expenditure during acute α2-adrenergic antagonism in obese subjects

“…Noradrenaline release is controlled through a negative feedback mechanism operating through presynaptic a 2 -adrenoceptors. 25 In rodent models of obesity, the a 2 adrenoceptor antagonist yohimbine increases energy expenditure, probably through to the activation of brown adipose tissue. 26 Few experiments have been conducted in non-rodent mammals or in humans.…”