Second Messenger Systems

2005-04-09T07:08:00.000-07:00

This article has been published by the International Biopharmaceutical Association www.ibpassociation.org

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Second messenger systems are complexes of regulatory (eg, G-proteins) and catalytic (eg, adenylate cyclase, phospholipase C) proteins, which are activated by NTs (first messengers) to form specific chemicals or second messengers (eg, cAMP, inositol triphosphate or IP3, diacylglycerol or DAG).

Adenylate cyclase-cAMP is the best known second messenger system. Here, the first messenger (NT, hormone) binds to the receptor activating a stimulatory G-protein (Gs) by displacing guanosine diphosphate (GDP) with guanosine triphosphate (GTP). G-proteins consist of alpha, beta, and gamma subunits; the alpha unit binds the guanine nucleotide and provides specificity for receptors. The activated protein amplifies the signal of the first messenger and activates adenylate cyclase. This enzyme converts adenosine triphosphate (ATP) to cAMP, which activates specific phosphorylating enzymes or protein kinases to produce the physiologic response. The action of cAMP is terminated by the enzyme phosphodiesterase. In addition to the stimulatory G-protein, inhibitory G-proteins (Gi) exist. By activation of a different receptor and this Gi, adenylate cyclase is inhibited. In each category, different G-proteins have been identified (Gs1, Gs2, Gs3 and Gi1, Gi2, Gi3).

Phosphoinositide system - generates 2 second messengers, IP-3 and DAG. Upon receptor stimulation and G-protein activation, phospholipase C is stimulated, which hydrolases membrane phosphatidyl inositol 4,5-biphosphate into IP-3 and DAG. IP-3 releases calcium from intracellular stores, and DAG activates protein kinase C. Effects on ion channels or phosphorylation of specific proteins causes the physiologic effects.

Pharmacology of Neurotransmission
Drugs can increase or decrease the synthesis, storage, release, or degradation of a specific NT, usually in all neurons in the body and brain. Such drugs are not selective in their action on a specific organ; in contrast, certain drugs can rather selectively stimulate (agonists) or block (antagonists) specific receptors and can be more selective (concentration dependent) in their effects.

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