Signal transduction second messengers activation

A completely different type of effect is observed in metabotropic receptors (bottom right). After binding of the transmitter, these interact on the inside of the postsynaptic membrane with Gproteins (see p. 384), which in turn activate or inhibit the synthesis of second messengers. Finally, second messengers activate or inhibit protein kinases, which phosphorylate cellular proteins and thereby alter the behavior of the postsynaptic cells (signal transduction see p.386). 

This interaction can be of several types If both receptors use a common signal transduction pathway, the activation can result in an additive response by the cell. Conversely, if simultaneous receptor activation triggers opposing signal transduction pathways, the outcome will be an attenuated cellular response. Other types of interactions may include the desensitization or activation of other receptor proteins or second messenger pathways. The final outcome of the activation of multiple signals is an integrated response by the cell. 

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

Depletion of ATP in the cells prevents maintenance of the membrane potential, inhibits the functioning of ion pumps, and attenuates cellular signal transduction (e.g., formation of second messengers such as inositol phos phates or cyclic AMP). A marked ATP depletion ultimately impairs the activ-itv of the cell and leads to ceil death. 

As with signal transduction and second messenger systems, the mechanism of gene activation allows for amplification of the hormone s effect. 

GM-CSF and IL-3 have been shown to compete for receptors in some types of cells (e.g. eosinophils and KG-1 cells), indicating some structural homology between GM-CSF and IL-3 receptors, perhaps because they share certain subunits or adapter proteins. GM-CSF occupancy results in phosphorylation of certain proteins, and because the receptor possesses no inherent kinase activity, receptor occupancy must be linked to kinase activity via the generation of second messenger molecules. Pretreatment of cells with pertussis toxin abolishes the effects of GM-CSF, indicating the involvement of G-proteins in signal transduction. Priming of neutrophil functions with GM-CSF involves the activation of phospholipases A2 and D. 

PLC is a generic name for a family of isoforms of an enzyme which remain membrane bound as the presence of phospholipids is required for activity. Signal transduction via PLC as the effector is mediated by not one but two second messengers inositol 1,4,5 triphosphate (IP3) and DAG, which are the products of hydrolysis of membrane phospholipid by PLC (Figure 4.18). 

In addition to its role as a bone component, calcium functions as a signaling substance. Ca "" ions act as second messengers in signal transduction pathways (see p. 386), they trigger exocytosis (see p. 228) and muscle contraction (see p. 334), and they are indispensable as cofactors in blood coagulation (see p. 290). Many enzymes also require Ca "" for their activity. The intracellular and extracellular concentrations of Ca "" are strictly regulated in order to make these functions possible (see B, C, and p.388). 

Action. cAMP is an allosteric effector of protein kinase A (PK-A, [3]). in the inactive state, PK-A is a heterotetramer (C2R2), the catalytic subunits of which (C) are blocked by regulatory units (R autoinhibition). When cAMP binds to the regulatory units, the C units separate from the R units and become enzymatically active. Active PK-A phosphorylates serine and threonine residues of more than 100 different proteins, enzymes, and transcription factors, in addition to cAMP, cCMP also acts as a second messenger, it is involved in sight (see p. 358) and in the signal transduction of NO (see p. 388). 

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