Cyclic AMP-protein kinase A cascade

England S, Bevan S, Docherty RJ 1996 PGE2 modulates the tetrodotoxin-resistant sodium current in neonatal rat dorsal root ganglion neurones via the cyclic AMP-protein kinase A cascade. Physiol 495 429-440... 

Xiao 1, Shen M, Colucci W. P,-Adrenergic receptor (AR) stimulation inhibits oq-AR-stimulated hypertrophic signaling in adult rat ventricular myocytes (ARVM) via activation of cyclic AMP-protein kinase A (PK A) cascade [abstract]. Circulation 2002 106 11-48. 

Cyclic AMP diffuses away from the membrane and engages its own target which is an inactive protein kinase, called cAMP dependent protein kinase or protein kinase A (PKA). The inactive PKA is a tetramer of two catalytic subunits and two regulatory subunits. Binding of cAMP to the regulatory subunits causes structural changes and the two regulatory subunits dissociate from the two catalytic sub-units. The now activated protein kinase A, that is the C subunit dimer, initiates a downstream cascade by... 

Figure 8 Simplified diagram of a signaling cascade that involves NE, BDNF, and CREB after NE acts on the postsynaptic fi-noradrenergic receptor. NE couples to a G protein (Gas), which stimulates the production of cAMP from adenosine triphosphate (ATP). This reaction is catalyzed by adenylate cyclase (AC). cAMP activates protein kinase A (PKA). Inside the cell, PKA phosphorylates (P) the CREB protein, which binds upstream from specific regions of genes and regulates their expression. BDNF is one target of cAMP signaling pathways in the brain. CRE, cyclic AMP regulatory element ER, endoplasmic reticulum, [reprinted from Reference 76 with permission of the author and the publisher, Canadian Medical Association].

Figure 21.17 Coordinate control of glycogen metabolism. Glycogen metabolism is regulated, in part, by hormone triggered cyclic AMP cascades. The sequence of reactions leading to the activation of protein kinase A ultimately activates glycogen degradalion. At the same time, protein kinase A also inactivates glycogen synthase, shutting down glycogen synthesis.

Figure 20-2. The mobilization of glycogen in the liver in response to hormonal signals. Binding of the hormones glucagon and/or epinephrine causes the activation of adenylate cyclase resulting in the production of cyclic AMP, which activates protein kinase A. By phosphorylation reactions, protein kinase A inactivates glycogen synthase, activates a cascade that results in active glycogen phosphorylase, and produces an active inhibitor of protein phosphatase 1.

At this juncture we would like to remind the reader that HMGR is an interconvertible enzyme, which exists in phosphorylated (inactive) and dephosphorylated (active) forms. The occurrence of these two forms is at the center of the activity of the enzyme. The active inactive interconversion involves a protein Kinase cascade which operates via cyclic AMP (cAMP) as a secondary messenger [26]. 

It is instructive to note that the biochemistry of the reactions that initiate the visual cascade and the glycogenolytic cascade is similar. The cyclic AMP-dependent protein kinase complex comprises the regulatory and catalytic components (R and C) for which the regulatory signal is the concentration of cyclic AMP. This binds to the regulatory component of the kinase (the R subunit) which then dissociates from the R-C complex. The C is now catalyti-cally active and catalyses the initial reaction in a cascade sequence which leads to activation of the target protein (phosphorylase). 

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