CAMP cascade

Alreja M, Aghajanian G. Pacemaker activity of locus coeruleus neurons whole-cell recordings in brain slices show dependence on cAMP and protein kinase A. Brain Res 1991 556 339—343. Shiekhattar R, Aston-Jones G. Modulation of opiate responses in brain noradrenergic neurons by cAMP cascade changes with chronic morphine. Neuroscience 1993 57 879-885. 

Glycogen phosphorylase isoenzymes have been isolated from liver, brain and skeletal muscle. All forms are subject to covalent control with conversion of the inactive forms (GP-b) to the active forms (GP-a) by phosphorylation on specific serine residues. This phosphorylation step, mediated by the enzyme phosphorylase kinase, is initiated by glucagon stimulation of the hepatocyte. Indeed, the same cAMP cascade which inhibits glycogen synthesis simultaneously stimulates glycogenolysis, giving us an excellent example of reciprocal control. 

In addition to 1-a-hydroxylase, the kidney also possesses a 24-hydroxylase which uses calcidiol as substrate the product of the reaction, 24,25 dihydroxy D3, is biologically inactive. This represents an important control point in the pathway. The activity of the 1-a-hydroxylase is promoted by calcium ions and the action of PTH acting via a G-protein/cAMP cascade. However, calcitriol itself simultaneously induces the 24-hydroxylase and suppresses 1-a-hydroxylase creating an effective feedback loop (Figure 8.12). 

One of the best-characterized effectors and second messenger systems is the cAMP cascade that can be either activated or inhibited by neurotransmit-ter/neuropeptide receptors, including those implicated in anxiety/stress such as CRE Receptors that activate cAMP synthesis couple with the stimulatory G protein, Gsa, and those that inhibit this second messenger couple with the inhibitory G protein, Gia, and these either stimulate or inhibit adenylyl cyclase, the effector enzyme responsible for synthesis of cAMP (Duman and Nestler 1999). There are at least nine different forms of adenylyl cyclase that have been identified by molecular cloning, each with a unique distribution in the brain. The different types of adenylyl cyclase are activated by Gsa as well as the diterpene forskolin, but are differentially regulated by Gia, the Py subunits, Ca, and by phosphorylation. This provides for fine control of adenylyl cyclase enzyme activity and regulation by other effector pathways. 

Ambrosini A, Tininini S, Barassi A, Racagni G, Sturani E, Zippel R. cAMP cascade leads to Ras activation in cortical neurons. Brain Res Mol Brain Res 2000 75 54-60. 

However, mechanisms involved in olfactory signaling seem much more diverse than hitherto expected. Recently, a subset of olfactory neurons has been described that lacks most of the elements for the AC/cAMP cascade these cells rather express distinct subtypes of guanylyl cyclase (GC-D) and phosphodiesterase (PDE2) (Juilfs et al., 1997), as well as a characteristic channel subtype (Meyer et al., 2000). These sensory neurons, which project to the so-called necklace... 

Pyruvate kinase catalyzes the third irreversible step in glycolysis. It is activated by fructose 1,6-bisphosphate. ATP and the amino acid alanine allosterically inhibit the enzyme so that glycolysis slows when supplies of ATP and biosynthetic precursors (indicated by the levels of Ala) are already sufficiently high. In addition, in a control similar to that for PFK (see above), when the blood glucose concentration is low, glucagon is released and stimulates phosphorylation of the enzyme via a cAMP cascade (see Topic J7). This covalent modification inhibits the enzyme so that glycolysis slows down in times of low blood glucose levels. 

During starvation, the priority is to conserve blood glucose for the brain and muscle. Thus, under these conditions, pyruvate kinase in the liver is switched off. This occurs because the hormone glucagon is secreted into the bloodstream and activates a cAMP cascade (see Topic J7) that leads to the phosphorylation and inhibition of this enzyme. 

The sense of smell, or olfaction, is remarkable in its specificity—it can, for example, discern stereoisomers of small organic compounds as distinct aromas. The 7TM receptors that detect these odorants operate in conjunction with a G protein that activates a cAMP cascade resulting in the opening of an ion channel and the generation of a nerve impulse. An outstanding feature of the olfactory system is its ability to detect a vast array of odorants. Each olfactory neuron expresses only one type of receptor and connects to a particular region of the olfactory bulb. Odors are decoded by a combinatorial mechanism—each odorant activates a number of receptors, each to a different extent, and most receptors are activated by more than one odorant. 

Kaminski NE (1998) Regulation of the cAMP cascade, gene expression and immune function by cannabinoid receptors. J Neuroimmunol 83 124-132... 

Iodide by an Xl-type mechanism inhibits both cAMP and the phospholipase G cascades (Figure 32.2). The inhibition of TSH, prostaglandin El (PGEl), cholera toxin and forskolin-activated cAMP cascade bears on Gs— adenylyl cyclase couple and on cAMP generation (Gochaux et al, 1987 Filetti and Rapoport, 1983 ... 

List the steps in a G protein-cAMP cascade that contribute to the amplification of the hormonal stimulus, and explain how the amplified response is achieved. 

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