Protein targeting exocytosis

Much evidence supports a role for these proteins in exocytosis. For instance, injection of recombinant SNAP into the squid giant axon increases vesicular exocytosis. Also, membrane SNAP-25 and syntaxin are both targets for botulinum toxin while the vesicule protein, synaptobrevin, is a target for tetanus and botulinum toxins both these toxins are well known for disrupting transmitter release. 

There are evidently several potential loci for the action of PKC in facilitating neurotransmitter release. The question is what are the protein targets/substrates for PKC that mediate these multiple mechanisms of regulation of exocytosis ... 

In humans, the hypothalamic-derived protein and the hormone noncovalent complexes are packaged in neurosecretory granules, then migrate along axons at a rate of 1 4 mm/h until they reach the posterior pituitary where they are stored prior to release into the bloodstream by exocytosis (67). Considerable evidence suggests that posterior pituitary hormones function as neurotransmitters (68) vasopressin acts on the anterior pituitary to release adrenocorticotropic hormone [9002-60-2] (ACTH) (69) as well as on traditional target tissues such as kidneys. Both hormones promote other important central nervous system (CNS) effects (9,70). 

Protein/peptide hormones are derived from amino acids. These hormones are preformed and stored for future use in membrane-bound secretory granules. When needed, they are released by exocytosis. Protein/peptide hormones are water soluble, circulate in the blood predominantly in an unbound form, and thus tend to have short half-lives. Because these hormones are unable to cross the cell membranes of their target tissues, they bind to receptors... 

Vesicular proteins and lipids that are destined for the plasma membrane leave the TGN sorting station continuously. Incorporation into the plasma membrane is typically targeted to a particular membrane domain (dendrite, axon, presynaptic, postsynaptic membrane, etc.) but may or may not be triggered by extracellular stimuli. Exocytosis is the eukaryotic cellular process defined as the fusion of the vesicular membrane with the plasma membrane, leading to continuity between the intravesicular space and the extracellular space. Exocytosis carries out two main functions it provides membrane proteins and lipids from the vesicle membrane to the plasma membrane and releases the soluble contents of the lumen (proteins, peptides, etc.) to the extracellular milieu. Historically, exocytosis has been subdivided into constitutive and regulated (Fig. 9-6), where release of classical neurotransmitters at the synaptic terminal is a special case of regulated secretion [54]. 

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. 

From the Golgi apparatus, the proteins are transported by vesicles to various targets in the cells—e.g., to lysosomes (4), the plasma membrane (6), and secretory vesicles (5) that release their contents into the extracellular space by fusion with the plasma membrane (exocytosis see p. 228). Protein transport can either proceed continuously (constitutive), or it can be regulated by chemical signals. The decision regarding which pathway a protein... 

The intracellular signaltransduction of ofi-adrenoceptors is effectuated by a G-protein-dependent activation of the phospholipase C. This enzyme cleaves phosphatidylinositol, a phospholipid present in cell membranes, into inositol-1,4-5-triphosphate (IP3) and diacylglycerol (DAG). IP3 is a strong inductor of intracellular calcium release which leads to an increase of smooth muscle tone or the liberation of hormones stored in vesicles. Noradrenaline which is released by exocytosis, spreads by diffusion only. Only a small fraction of the total amount of the transmitter released will actually reach the postsynaptic membrane and bind to its specific receptors. Another fraction escapes the synapic cleft by diffusion and is finally enzymatically degraded in the interstitial fluid. Another fraction is taken up postsynaptically and metabolized enzymatically by the target cells (uptake 2). By far most of the transmitter (90%) is actively taken up by the releasing neuron itself (uptake 1 or neuronal re-uptake). In the... 

These paralytic effects have been attributed to the proteolytic activity of BoNT light chain (LC) on protein substrates required for vesicular exocytosis. BoNT LC inhibits neurotransmitter exocytosis through its zinc-dependent endoproteolytic activity. The LCs of the various neurotoxin serotypes possess distinct molecular targets within the peripheral cholinergic nerve termainals (Schiavo et al, 1992, 1993a, b, 1994, 1995 Yamasaki et al, 1994). The endoproteolytic activities of the different toxin LCs produce similar flaccid paralytic effects. 

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