Protein kinases, second messenger systems

Two major second messenger systems have been evolved. When the a-sub-unit is temporarily linked to adenylate cyclase, the enzyme is activated and catalyzes the transformation of ATP to cAMP. This second messenger activates a specific protein kinase, which in turn phosphorylates target proteins in the cell leading to the overall physiological response. Such a pathway is utilized by the /1-adrenoceptor, dopaminergic, and prostaglandin receptors, etc. 

In humans the intronless gene encoding HR2 is located on chromosome 5. The human HR2 is a protein of 359 amino acids coupled to both adenylate cyclase and phosphoinositide second messenger systems by separate GTP-dependent mechanisms including Ga and also induces activation of c-Fos, c-Jun PKC and p70S6 kinase [16], Studies in different species and several human cells demonstrated that inhibition of characteristic features of the cells by primarily cAMP formation dominates in HR2-dependent effects of histamine. 

Water-soluble hormones must transmit signals to affect metabolism and gene ejcpression without themselves entering the cytoplasm. They often do so via second messenger systems that, in turn, activate protein kinases. 

The sequence of events (illustrated in Figure 1-9-2) leading from receptor to activation of the protein kinase via the cAMP and PIPj second messenger systems is as follows ... 

Mood disorders characterized by elevations of mood above normal as well as depressions below normal are classically treated with lithium, an ion whose mechanism of action is not certain. Candidates for its mechanism of action are sites beyond the receptor in the second messenger system, perhaps either as an inhibitor of an enzyme, called inositol monophosphatase, involved in the phosphatidyl inositol system as a modulator of G proteins, or even as a regulator of gene expression by modulating protein kinase C (Fig. 7—22). 

Effect of lithium on the IP3 and DAG second-messenger system. The schematic diagram shows the synaptic membrane of a neuron. (PIP2, phosphatidylinositol-4,5-bisphosphate PLC, phospholipase-C G, coupling protein EFFECTS, activation of protein kinase C, mobilization of intracellular Ca2+, etc.) Lithium, by inhibiting the recycling of inositol substrates, may cause... 

Although the primary mode of action of ACTH is via cyclic AMP and cyclic AMP-dependent protein kinase (A-kinase), calcium probably plays a secondary role in enhancing and modulating the action of ACTH via the A-kinase pathway. This is discussed later in the consideration of the interaction of the A-kinase pathway of activation by ACTH and other second messenger systems involving calcium and protein kinase C. 

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