Adenylate cyclase enzyme, effect

An example of a hormone that exerts its effects through a surface receptor-second messenger system is ACTH.36 ACTH is a polypeptide that binds to a surface receptor on adrenal cortex cells. The surface receptor then stimulates the adenylate cyclase enzyme to increase production of cAMP, which acts as a second messenger (the hormone was the first messenger), and increases the activity of other enzymes within the cell to synthesize adrenal steroids such as cortisol. For a more detailed description of surface receptor-second messenger systems, see Chapter 4. 

Glucagon appears to exert its effects on liver cells by a classic adenyl cyclase-cyclic adenosine monophosphate (cAMP) second messenger system (see Chapter 4).93 Glucagon binds to a specific receptor located on the hepatic cell membrane. This stimulates the activity of the adenyl cyclase enzyme that transforms adeno-... 

Synaptic membrane-bound protein kinase activity is regulated by both cAMP and Ca + (106,107). Opiates might thus alter protein kinase activity by reducing Ca + availability, either directly or indirectly via adenylate cyclase. Enzyme induced protein phosphorylation is reported to cause altered membrane ion permeability and thus changes in neuronal excitability. Direct opiate effects on the enzyme could thus produce changes in Ca + distribution such as those discussed previously. 

Prostacyclin and its analogues also function by increasing the level of platelet cAMP, presumably by activation of the enzyme adenyl cyclase. A chemically stable analogue of prostacyclin called Iloprost has been effective in preventing consumption of platelets (71). 

Hydrolysis of triacylglycerides in tissues is effected by a tissue enzyme, tri-acylglyceride lipase, which hydrolyzes triacylglycerides to glycerol and free fatty acids. There are a variety of tissue lipases that differ primarily in their optimum pH and their location in the cell. The acidic lipase is contained in lysosomes the basic lipase, in microsomes and the neutral lipase, in cytoplasm. A specific feature of the tissue lipase is its sensitivity to hormones which, by activating adenylate cyclase, elicit the transition of the inactive tissue lipase to its active... 

It is obvious that Li+ has several inhibitory effects on the adenylate cyclase-dependent second-messenger system. Many of these influences can be counteracted by the addition of Mg2+, therefore it is probable that Li+ is competing for Mg2+ binding sites on, and thereby interfering with the activity of, the catalytic enzyme itself and/or of the associated G proteins. 

Mehorta and coworkers (1989) observed that isolated fractions of brain and heart cells from rats orally administered 0.5-10 mg endrin/kg showed significant inhibition of Ca+2 pump activity and decreased levels of calmodulin, indicating disruption of membrane Ca+2 transport mechanisms exogenous addition of calmodulin restored Ca+2-ATPase activity. In vitro exposure of rat brain synaptosomes and heart sarcoplasmic reticuli decreased total and calmodulin-stimulated calcium ATPase activity with greater inhibition in brain preparations (Mehorta et al. 1989). However, endrin showed no inhibitory effects on the calmodulin-sensitive calcium ATPase activity when incubated with human erythrocyte membranes (Janik and Wolf 1992). In vitro exposure of rat brain synaptosomes to endrin had no effect on the activities of adenylate cyclase or 3, 5 -cyclic phosphodiesterase, two enzymes associated with synaptic cyclic AMP metabolism (Kodavanti et al. 1988). 

Metabotropic receptors, in contrast, create their effects by activating an intracellular G protein. The metabotropic receptors are monomers with seven transmembrane domains. The activated G protein, in turn, may activate an ion channel from an intracellular site. Alternately, G proteins work by activation or inhibition of enzymes that produce intracellular messengers. For example, activation of adenylate cyclase increases production of cyclic adenosine monophosphate (cAMP). Other effector mechanisms include activation of phospholipases, diacylglycerol, creation of inositol phosphates, and production of arachidonic acid products. Ultimately, these cascades can result in protein phosphorylation. 

G proteins are divided into several types, depending on their effects. Stimulatory G proteins (Cs) are widespread. They activate adenylate cyclases (see below) or influence ion channels. Inhibitory G proteins (Cj) inhibit adenylate cyclase. G proteins in the Gq family activate another effector enzyme—phospholipase c (see p. 386). 

Apart from forskolin, a number of other manoyl oxides have been shown to interact with the AC enzyme system. Biotransformation of certain ent- 3-epi-manoy oxides by Curvularia lunata resulted in compounds functionalized in C-3 or in C-3 and C-12, which exhibited an AC stimulatory effect, although milder than that of forskolin (about 30 times less) [173]. The same activity was also ascribed to some synthetic derivatives of en/-8a-hydroxy-13 (16), 14 dien-18-oic acid methyl ester [178,179], The biotransformation of ent-manoyl oxide-16-hydroxy 18-oic acid methyl ester with Rhizopus nigricans, however, resulted in carbomanoyl oxide which showed a selective inhibitory action on the activity of adenylate cyclase depending on the material initially used to stimulate the enzyme. This manoyl oxide inhibited the activity of the enzyme previously stimulated by forskolin but not by glucagon. A manoyl oxide ent-3fi, 6/ -dihydroxy-13-e/ z-manoyl oxide) which also inhibited the activity of AC, was produced from the biotransformation of... 

As noted, the labdanes display a broad spectrum of biochemical and pharmacological activities, suggesting that they may significantly affect the function of the immune system and inflammatory cells. The labdanes may affect critical enzymes such as adenylate cyclase, protein kinases and phospholipase A2, which are intimately involved in signal transduction and cell activation processes. Much of the information on labdane-type diterpene effects has been provided by forskolin and mainly in in vitro systems. 

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