Insulin Adenylate cyclase

We have tested the hypothesis that insulin inhibits the stimulatory effect of parathyroid hormone (PTH) on calcium reabsorption in the distal nephron. PTH is known to enhance calcium transport in renal cells, probably by stimulation of adenylate cyclase and subsequent increases in 3 5 cyclic AMP productoin. Since insulin had been observed to inhibit PTH-stimulated increases in kidney cyclic AMP levels in vitro (24) we investigated whether insulin-mediated hypercalciuria was dependent on the presence of PTH in vivo. 

Glucagon stimulates adenylate cyclase activity and this increases the concentration of cyclic AMP. Insulin antagonises this effect via an increase in the activity of cyclic AMP phosphodiesterase, which hydrolyses cyclic AMP to AMP, which results in a decrease in the concentration of cyclic AMP (Figure 6.34). 

Figure 6.34 Effects of glucagon and insulin on the cyclic AMP level. Glucagon increases the activity of adenylate cyclase, which increases the concentration of cyclic AMP whereas insulin activates the phosphodiesterase which hydrolyses cyclic AMP to form AMP. Cyclic AMP activates protein kinase A.

Metabolism. The nucleotide cAMP (adenosine 3, 5 -cyclic monophosphate) is synthesized by membrane-bound adenylate cyclases [1] on the inside of the plasma membrane. The adenylate cyclases are a family of enzymes that cyclize ATP to cAMP by cleaving diphosphate (PPi). The degradation of cAMP to AMP is catalyzed by phosphodiesterases [2], which are inhibited by methylxanthines such as caffeine, for example. By contrast, insulin activates the esterase and thereby reduces the cAMP level (see p. 388). 

Lithium blocks the release of thyroxine (T4) and triiodothyronine (T3) mediated by thyrotropin (Kleiner et ah, 1999). This results in a decrease in circulating T4 and T3 concentrations and a feedback increase in serum thyrotropin concentration. It also inhibits thyrotropin-stimulated adenylate cyclase activity (Kleiner et ah, 1999). Lithium has varying effects on carbohydrate metabolism. Increased and decreased glucose tolerance and decreased sensitivity to insulin have been observed (Van derVelde Gordon, 1969). In animals, lithium decreases hepatic cholesterol and fatty acid synthesis. 

Glucagon and insulin bind to specific receptors on the outer plasma membrane of a target cell. In the case of glucagon, this binding indirectly stimulates the enzyme adenylate cyclase, on the inner surface of the membrane, to catalyze the production of cyclic AMP. Depending on the cell type,... 

Livingstone, C., A.R. McLellan, M.A. McGregor, A. Wilson, J.M. Connell, M. Small, G. Milligan, K.R. Paterson, and M.D. Houslay. 1991. Altered G-protein expression and adenylate cyclase activity in platelets of non-insulin-dependent diabetic (NIDDM) male subjects. Biochim. Biophys. Acta 1096 127-133. 

Other evidence for the involvement of a G-protein in the action of insulin has come from studies by Walaas and co-workers [104]. They have demonstrated that insulin stimulated the activity of a cyclic AMP-dependent protein kinase activity in sarcolemma membranes. As this effect of insulin was enhanced if micromolar concentrations of GTP-binding protein were present, they suggested that a guanine nucleotide regulatory protein was involved in the hormonal control of this kinase. Indeed, cholera toxin also appeared to obliterate this action of insulin, as it did the effect of insulin on liver adenylate cyclase and the peripheral plasma membrane cyclic AMP phosphodiesterase in liver. 

The mobilisation of adipose lipid stores is inhibited by numerous stimuli, the most significant being insulin (through the inhibition of adenyl cyclase activity). In a well-fed individnal, insulin release prevents the inappropriate mobilisation of stored lipid instead any excess fat and carbohydrate are incorporated into the triacylglycerol pool within adipose tissne. 

The initial event in the utilization of fat as an energy source is the hydrolysis of triacylglycerols by lipases, an event referred to as lipolysis. The lipase of adipose tissue are activated on treatment of these cells with the hormones epinephrine, norepinephrine, glucagon, and adrenocorticotropic hormone. In adipose cells, these hormones trigger 7TM receptors that activate adenylate cyclase (Section 15,1.3 ). The increased level of cyclic AMP then stimulates protein kinase A, -which activates the lipases by phosphorylating them. Thus, epinephrine, norepinephrine, glucagon, and adrenocorticotropic hormone induce lipolysis (Figure 22.6). In contrast, insulin inhibits lipolysis. The released fatty acids are not soluble in blood plasma, and so, on release, serum albumin binds the fatty acids and serves as a carrier. By these means, free fatty acids are made accessible as a fuel in other tissues. 

LPS increases the transport of cisplatin, insulin, and the HIV-1 viral coat glycoprotein gpl20, but not of TNF or pituitary adenylate cyclase activating polypeptide (Banks et al., 1999 Minami et al, 1998 Nonaka et al., 2005 Osburg et al., 2002 Xaio et al., 2001). LPS affects leptin transport (Nonaka et al., 2004) through peripheral mechanisms and increases pituitary adenylate cylcase activating polypeptide binding to receptors on the BBB but does not alter transport. CNS injuries such as ischemia or trauma to the spinal cord induce a cascade of events, which can affect the transport of neuroimmune substances across the BBB as discussed below. 

Its primary action is inhibiting the release of GH from the pituitary gland. Somatostatin al.so suppresses the release of both insulin and glucagon. It causes a decrease in both cAMP levels and adenylate cyclase activity. It also inhibits calcium ion influx into the pituitary cells and suppresses glucose-induced pancreatic insulin secretion by activating and deactivating potassium ion and calcium ion permeability, respcc-tively. The chemistry. SARs, and potential clinical applications have been reviewed.--- ... 

Modulation of Insulin Secretion via Adenylate Cyclase and Phospholipase C (PLC). 92... 

Secretion of insulin results from the action of initiators and modulators on the secretory mechanism. Whereas initiators cause the discharge of insulin by depolarization of the B-cell and subsequent influx of Ca +, modulation (i.e. amplification and/or attenuation) is mediated mainly by activating and/or inactivating the adenylate cyclase and/or phospholipase C systems. 

Similar to other tissues, insulin-producing cells possess an adenylate cyclase-cAMP system including stimulatory and inhibitory G-proteins and phosphodiesterases. 

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