Calmodulin neurotransmitters

NO is a gaseous neurotransmitter implicated in signaling in the central and peripheral nervous system as well as in the immune system and the vasculature. NO is formed from L-arginine by nitric oxide synthase (NOS). There are three isoforms of NOS. All isoforms require NADPH as a cofactor, use L-arginine as a substrate, and are inhibited by Nw-nitro-L-arginine methyl ester (L-NAME). The three isoforms are separate gene products. One isoform of NOS is a cytosolic, calcium/calmodulin-independent, inducible enzyme (iNOS). It is found in macrophages, neutrophils, vascular smooth muscle, and endothelia. The iNOS... 

Calmodulin, a calcium binding protein, is involved in Ca2+-dependent regulation of several synaptic functions of the brain synthesis, uptake and release of neurotransmitters, protein phosphorylation and Ca+2 transport. It reacts with TET, TMT and TBT which then inactivates enzymes like Ca+2-ATPase and phosphodiesterase. In vitro studies indicated TBT was greater at inhibiting calmodulin activity than TET and TMT, whereas in vivo the order was TET > TMT > TBT. This may be due to the greater detoxification of TBT (66%) in the liver before moving to other organs30,31. 

Ca2+,calmodulin-dependent May transiently associate with synaptic vesicles to phosphorylate synapsins and rabphilin-3A. May regulate various protein kinases I and II steps in neurotransmitter release. 

The synthesis of 5-HT can increase markedly under conditions requiring more neurotransmitter. Plasticity is an important concept in neurobiology. In general, this refers to the ability of neuronal systems to conform to either short- or long-term demands placed upon their activity or function (see Plasticity in Ch. 53). One of the processes contributing to neuronal plasticity is the ability to increase the rate of neurotransmitter synthesis and release in response to increased neuronal activity. Serotonergic neurons have this capability the synthesis of 5-HT from tryptophan is increased in a frequency-dependent manner in response to electrical stimulation of serotonergic soma [7]. The increase in synthesis results from the enhanced conversion of tryptophan to 5-HTP and is dependent on extracellular calcium ion. It is likely that the increased 5-HT synthesis results in part from alterations in the kinetic properties of tryptophan hydroxylase, perhaps due to calcium-dependent phosphorylation of the enzyme by calmodulin-dependent protein kinase II or cAMP-dependent protein kinase (PKA see Ch. 23). 

Most protein serine-threonine kinases undergo autophosphorylation. The autophosphorylation of most protein kinases is associated with an increase in kinase activity [4, 10]. In some instances, such as with the RII subunit of PKA, autophosphorylation represents a positive feedback mechanism for kinase activation, in this case by enhancing the rate of dissociation of the RII and C subunits. In the case of CaMKII, autophosphorylation causes the catalytic activity of the enzyme to become independent of Ca2+ and calmodulin. This means that the enzyme, activated originally in response to elevated cellular Ca2+, remains active after Ca2+ concentrations have returned to baseline. By this mechanism, neurotransmitters that activate CaMKII can produce relatively long-lived alterations in neuronal function. In other instances, such as with the receptor-associated protein tyrosine kinases (discussed in Ch. 24), autophosphorylation is an obligatory step in the sequence of molecular events through which those kinases are activated and produce physiological effects. 

Hormonal actions on target neurons are classified in terms of cellular mechanisms of action. Hormones act either via cell-surface or intracellular receptors. Peptide hormones and amino-acid derivatives, such as epinephrine, act on cell-surface receptors that do such things as open ion-channels, cause rapid electrical responses and facilitate exocytosis of hormones or neurotransmitters. Alternatively, they activate second-messenger systems at the cell membrane, such as those involving cAMP, Ca2+/ calmodulin or phosphoinositides (see Chs 20 and 24), which leads to phosphorylation of proteins inside various parts of the target cell (Fig. 52-2A). Steroid hormones and thyroid hormone, on the other hand, act on intracellular receptors in cell nuclei to regulate gene expression and protein synthesis (Fig. 52-2B). Steroid hormones can also affect cell-surface events via receptors at or near the cell surface. 

Sodium and potassium are not the only ions which can participate in pumps and channels. Calcium is also pumped, channeled, exhanged,and stored. See Figure 23. Calcium concentration within the cell cytoplasm is very low. This allows the calcium to play a pivotal role in cellular activity. The cytoplasmic protein calmodulin binds and stores calcium ion. Various intracellular structures and organelles such as the mitochondria and sarcoplasmic reticulum also store calcium. Calcium is vital to such functions as the release of neurotransmitters from nerve cells. There are at least seven known modes of biochemical action for this ion, one of the most important of which involves stimulation of cardiac muscle protein (actin-myosin). Certain types of angina (heart pain) are believed to be caused by abnormal stimulation of cardiac arteries and muscle (coronary spasm) A relatively new class of drugs, known as the calcium channel blockers, has brought relief from pain and arrhythmias (irregular heart beats). 

The hereditary absence of phenylalanine hydroxylase, which is found principally in the liver, is the cause of the biochemical defect phenylketonuria (Chapter 25, Section B).430 4308 Especially important in the metabolism of the brain are tyrosine hydroxylase, which converts tyrosine to 3,4-dihydroxyphenylalanine, the rate-limiting step in biosynthesis of the catecholamines (Chapter 25), and tryptophan hydroxylase, which catalyzes formation of 5-hydroxytryptophan, the first step in synthesis of the neurotransmitter 5-hydroxytryptamine (Chapter 25). All three of the pterin-dependent hydroxylases are under complex regulatory control.431 432 For example, tyrosine hydroxylase is acted on by at least four kinases with phosphorylation occurring at several sites.431 433 4338 The kinases are responsive to nerve growth factor and epidermal growth factor,434 cAMP,435 Ca2+ + calmodulin, and Ca2+ + phospholipid (protein kinase C).436 The hydroxylase is inhibited by its endproducts, the catecholamines,435 and its activity is also affected by the availability of tetrahydrobiopterin.436... 

The secretion of neurotransmitters from synaptic vesicles at neuroterminals requires entry of Ca2+ into the nerve terminal. Calmodulin is also involved,423 and calcium-dependent424 and calcium-independent425 sites for calmodulin have been found on cholinergic synaptic vesicles from the electric organ of Narcine brasiliensis. Again it appears that phosphorylation of a protein is required. 

In cell culture preparations, diphenylhydantoin, carbamazepine and valproate have been shown to reduce membrane excitability at therapeutically relevant concentrations. This membrane-stabilizing effect is probably due to a block in the sodium channels. High concentrations of diazepam also have similar effects, and the membrane-stabilizing action correlates with the action of these anticonvulsants in inhibiting maximal electroshock seizures. Intracellular studies have shown that, in synaptosomes, most anticonvulsants inhibit calcium-dependent calmodulin protein kinase, an effect which would contribute to a reduction in neurotransmitter release. This action of anticonvulsants would appear to correlate with the potency of the drugs in inhibiting electroshock seizures. The result of all these disparate actions of anticonvulsants would be to diminish synaptic efficacy and thereby reduce seizure spread from an epileptic focus. 

Calcium/calmodulin-dependent protein kinase II (CaM kinase II) is a mediator of synaptic and cytoskeletal function as well as neurotransmitter release. The reduced CaM kinase II activity observed following normothermic ischemia is not seen under conditions of intraischemic hypothermia (57,110). Ubiquitin, a small protein involved in the catabolism of other abnormal proteins, is decreased following ischemia this may lead to an accumulation of abnormal proteins that affect cell function. Intraischemic hypothermia induces a significant restitution of ubiquitin compared to the normothermic condition (111). 

Calmodulin Sepharose Calmodulin Calmodulin-binding proteins, neurotransmitters Pharmacia... 

Figure 7.3. Mechanism of transmitter release, a Thepresynap-tic action potential opens voltage-gated Ca channels. Ca triggers exocytosis of neurotransmitters stored in piesynaptic vesicles. b Some proteins (out of mat r more) that are involved in exocytosis. Ca is involved at multiple stages. By binding to calmodulin (CaM), it promotes phosphorylation of synapsin, which primes the transmitter vesicle but does not immediately lead to exocytosis. Adhesion of primed vesicles to the presynap-tic membrane is mediated by synaptobrevin and other SNARE proteins. Synaptotagmin is activated directly by Ca and participates in the final step of secretiom...

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