Second-messenger molecules

Ligand regulation. There are no clear cases for smooth muscle where a first or a second messenger molecule binding to a Ca channel of any type causes an activation (opening) of the channel or a shift of the voltage sensitivity. However, these remain as viable possible modes of regulation. 

The neurotransmitters of the ANS and the circulating catecholamines bind to specific receptors on the cell membranes of effector tissue. Each receptor is coupled to a G protein also embedded within the plasma membrane. Receptor stimulation causes activation of the G protein and formation of an intracellular chemical, the second messenger. (The neurotransmitter molecule, which cannot enter the cell, is the first messenger.) The function of intracellular second messenger molecules is to elicit tissue-specific biochemical events within the cell that alter the cell s activity. In this way, a given neurotransmitter may stimulate the same type of receptor on two different types of tissue and cause two different responses due to the presence of different biochemical pathways within each tissue. 

The phospholipases (PLC) isozymes cleave the phosphodiester bond in phos-phatidyl-inositol-4,5-bisphosphate (PIP2) releasing two second messenger molecules inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) as shown before. The /1-isozyme are controlled by the Ga or G y subunits of the heterotrimeric G-proteins coupled to surface receptors. The y-isozymes are substrates for tyrosine kinases, such as growth factors. 

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. 

Once synthesized, NO behaves somewhat differently from classical neurotransmitters. NO is not released from neurons in a Ca +-dependent exocytotic process rather, it diffuses freely out of the neuron and to the next neuron. Once it reaches its target enzyme, NO does not interact with specific membrane-associated receptor proteins instead, it interacts with second-messenger molecules in the receiving neuron... 

The intracellular activation of enzymes in a signaling chain can lead to the formation of diffusible chemical signaling molecules in the cell. These intracellular signaling molecules are also termed second messengers. The second messenger molecules activate and recruit cognate enzymes for the further signal transduction. 

The substrates of the MAP kinase pathway are very diverse and include both cytosolic and nuclear localized proteins. Phospholipase A2 and transcription factors of the Ets family are well characterized substrates of the ERK pathway. Phosphorylation of a Ser residue of phospholipase A2 by ERK proteins leads to activation of the lipase activity. Consequently, there is an increase in release of arachidonic acid and of lyso-phospholipids, which can act immediately as diffusible signal molecules or may represent first stages in the formation of second messenger molecules. 

Phospholipase C (PTC, EC 3.1.4.3) catalyzes the hydrolysis of the phosphodiester bond in phospholipids. It releases the second messenger molecule diacylglycerin (DAG) important in the signal transduction cascade and a phosphorylated headgroup . The active site of the enzyme contains three Zn ions with two of them in close proximity. Only few crystal structures are solved until now " . ... 

Thus, the transfer of first messenger to second messenger is accomplished by means of a molecular cascade neurotransmitter to neurotransmitter receptor (Fig. 2—25) neurotransmitter receptor to G protein (Fig. 2—26) binary complex of two receptors to enzyme (Fig. 2—27) and enzyme to second-messenger molecule (Fig. 2-28). 

The second messenger molecules Ca2+ and cyclic AMP (cAMP) provide major routes for controlling cellular functions. In many instances, calcium (Ca2+) achieves its intracellular effects by binding to the receptor protein calmodulin. Calmodulin has the ability to associate with and modulate different proteins in a Ca2+-dependent and reversible manner. Calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE, EC 3.1.4.17) is one of the key enzymes involved in the complex interactions that occur between the cyclic-nucleotide and Ca2+ second messenger systems (see Figure 13.2). CaMPDE exists in different isozymic forms, which exhibit distinct molecular and catalytic properties. The differential expression and regulation of individual phosphodiesterase (PDE) isoenzymes in different tissues relates to their function in the body. 

As discussed above, two of the established effectors of the Ga limb of heterotrimeric G-proteins are adenylate cyclase (AC) and phospholipase C (PLCP), which, on stimulation, lead to the generation of the second-messenger molecules, cAMP and DAG/IP3, respectively. Through the respective activation of cAMP-dependent protein kinase (PKA) and Ca2+/phospholipid-dependent protein kinase (PKC), GPCRs coupled to AC and PLCp have the potential to effect indirect modulation of neurotransmitter release by phosphorylation of substrate proteins involved in the... 

Two stages of amplification occur in the G-protein-mediated signal response. First, a single ligand-receptor complex can activate many G proteins. Second, the G-protein-activated adenylyl cyclase or phospholipase synthesizes many second messenger molecules. Some of these intracellular second messengers and their effects are given in Table 6.2. 

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