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a1-adrenoceptors are of particular interest therapeutically because of their important role in the control of blood pressure. All a-adrenoceptors consist of single polypeptide chains with 7 membrane spanning domains, and are members of the G-protein coupled receptor superfamily.

Diagram from TIPS, March 1999[235], No.3, pp.87-126 ISSN 0165-6147

a1- adrenoceptors are found throughout the body, they are found in the brain where their functional role is not yet clear, they also play critical roles elsewhere in controlling contraction and growth of smooth and cardiac muscle.

There are three subtypes of the a1 receptor: a1A, a1B, and a1D. Uppercase letters are used to denote 'functionally defined' subtypes while lowercase is used to denote 'molecularly defined' subtypes. Most tissues express mixtures of the three subtypes, but the relative expression levels have been found to be different in different reports. These subtypes appear to coexist in different densities and ratios, and in most cases responses to a1-adrenoceptor selective agonists are probably due to activation of more than one subtype.

The affinities and selectivities of drugs for a1- adrenoceptor subtypes have been determined primarily by competition for radioligand binding to heterologously expressed recombinant subtypes. Most antagonists, including prazosin, show little or no selectivity between the three known a1-adrenoceptor subtypes. However, a variety of drugs with varying degrees of selectivity have been found. Studies suggest that noradrenaline and adrenaline activate all three a1 -adrenoceptor subtypes with similar potencies, and that synthetic agonists show significant selectivity between the subtypes.

Investigative research into the function of the various domains and/or amino acid residues of the adrenoceptors has produced a number of findings. The aspartate in the third transmembrane domain and the two serines in the fifth transmembrane domain that are conserved in all catecholamine receptors probably interacts with the protonated amine and two hydroxyls of the catecholamines. Using selective a1A agonists (e.g. oxymetazoline) Hwa et al (1995) used site directed mutagenesis to identify critical residues in a1A and a1B -adrenoceptors that are responsible for apparent differences in agonist binding potency. The results showed that conversion of alanine to valine in the fifth transmembrane domain and leucine to methionine in the sixth transmembrane domain of the a1B subtype increased this receptors affinity towards the selective a1A agonists until its affinity became similar to that of the a1A subtype. These two residues are therefore critical in subtype selective agonist binding, and may interact structurally within the receptor. Other studies suggest that the fifth transmembrane domain and a portion of the second extracellular loop are critically important in subtype selective antagonist binding. This kind of evidence suggests that a1 -adrenoceptor antagonists may bind near the surface of the receptor, rather than deep within the transmembrane domains like the agonists.

a -adrenoceptors are G-protein coupled receptors. The a1 class of adrenoceptors belong to the Gq/11 type of G-protein. An agonist acting at the a1-adrenoceptor binding site causes Gq/11 to activate phospholipase C dependent hydrolysis of phosphotidyl inositol 4,5, biphosphate. The conversion of this compound by phospholipase C results in the generation of 1) Inositol triphosphate, and 2) Diacyl glycerol (DAG). 1) Inositol triphosphate acts to release calcium from intracellular stores in the sarcoplasmic reticulum. 2) Diacyl glycerol synergises with calcium to activate protein kinase C which phosphorylates specific target proteins in the cell to change their function.

Diagram from H.Zhong, K.P. Minneman/European Journal of Pharmacology 375 (1999) 261-276

a1 adrenoceptors have been implicated in other signalling pathways including; calcium influx, arachadonic acid release, and mitogenic activity. a1-adrenoceptors may couple directly to activation of calcium channels in certain cells. Activation of a1-adrenoceptors leads to potentiation of a calcium current in a protein kinase C dependent manner.

Phospholipase A2 is an enzyme responsible for the release of arachidonic acid from phospholipids. a1B and a1D adrenoceptors have been shown to couple to phospholipase A2 and cause the activation of this enzyme through a pertussis toxin - sensitive pathway in CHO cells.

Mitogenic activity refers to cell growth and the mechanisms underlying it. G-protein coupled receptors, including a1-adrenoceptors have been shown to have mitogenic activity through mitogen activated protein kinase pathways.

Diagram from H.Zhong, K.P. Minneman/European Journal of Pharmacology 375 (1999) 261-276

(Mitogenic signaling mechanisms activated by growth factor and G-protein coupled receptors)