Effector enzymesadenylate cyclase

Eight adenylate cyclase isoenzymes have now been purified from mammalian sources (T.abl.e 2).(9) These proteins have molecular weights of approximately 120 000 and a complex topology within the membrane, consisting of a short cytoplasmic amino terminus followed by six transmembrane spans, a large cytoplasmic domain, a second set of six transmembrane spans, and a large intracellular carboxyl terminus domain (Fig, 4). This structure bears a striking resemblance to that of membrane transporter proteins. The transmembrane domains are not highly conserved between adenylate cyclases and share little or no homology with the highly conserved transmembrane domains of ion channels. The isoenzymes can be divided into three groups based on sequence similarities and shared regulatory properties. The first group, comprising types I, III, and VIII, are sensitive to stimulation by calcium ions together with its binding protein calmodulin, and to a lesser extent by G s. Type I is inhibited by bg-units while type III, which is found in large quantities in olfactory neurones, is insensitive to bg. The second group, comprising types II, IV, and VII, are activated by as and synergistically by bg, and have thus been proposed to act as 'coincidence detectors', i.e. molecules that integrate messages derived from different sources. This may account for the increases in cAMP formation observed in the hippocampus as a result of activation of receptors that are not coupled to G s, such as the serotonin 5-HT1A receptor. Brain tissue possesses large quantities of G o, representing 0.5 per cent of total brain protein, and dissociation of this G protein yields large quantities of bg which will then act synergistically with a s to activate adenylate cyclase. The third group, comprising types V and VI, are activated by a s and inhibited by ai and also by calcium ions.

Fig. 4 The structure of adenylate cyclase. The twelve cylinders represent membrane-spanning domains divided into the two sets M and M2. The amino terminus N is cytoplasmic and there are two large cytoplasmic domains C-, and C2. Each of these is divided into regions of high amino acid similarity among all members of the family, indicated in bold and labelled C 1a and C2a; less conserved regions are labelled C 1b and C2b. (Reproduced with permission from R. Taussig and A.G. Gilman (1995). Mammalian membrane-bound adenylyl cyclases. Journal of Biological Chemistry, 270, 1-4.)

Figure.5 illustrates the action of adenylate cyclase type III as a coincidence detector. (10) Interaction of odorants with their receptors in the nasal epithelium leads to dissociation of the G protein Golf, a member of the Gs family, into bg- and a-units, which then activate adenylate cyclase. Simultaneous activation of the inositol-1,4,5-trisphosphate pathway leads to release of calcium ions, which bind to calmodulin and result in further activation of the adenylate cyclase enzyme.

Calmodulin is abundant in olfactory neurones and can lead to generation of cAMP levels three to six times greater than those induced by a mixture of odorants. Activation of type III adenylate cyclase by calmodulin is most effective when the enzyme is associated with the activated guanosine-triphosphate-containing a-subunit of Golf, thus allowing substantial amplification of the odorant signal.

Fig. 5 Dual activation of olfactory adenylate cyclase (AC) type III by odorant-activated G olf and Ca2+-calmodulin resulting from odorant-induced synthesis of inositol trisphosphate (IP3). The odorants interact with odorant receptors (OR), which are coupled either to AC or to phospholipase C (PLC). Abbreviations as in Fig. 2. (Reproduced with permission from R.R.H. Anholt (1994). Signal integration in the nervous system: adenylate cyclases as molecular coincidence detectors. Trends in Neuroscience, 17, 37-41.) Printed with permission from Elsevier Science.

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