Vesicles release

At most synapses a conventional NT is synthesised from an appropriate precursor in the nerve terminal, stored in vesicles, released, acts on postsynaptic receptors and is... 

Yao I, Takagi H, Ageta H, et al. SCRAPPER-dependent ubiquitination of active zone protein RIM1 regulates synaptic vesicle release. Cell 2007 130 943-957. 

Synthesis of noradrenaline (norepinephrine) is shown in Figure 4.7. This follows the same route as synthesis of adrenaline (epinephrine) but terminates at noradrenaline (norepinephrine) because parasympathetic neurones lack the phenylethanolamine-N-methyl transferase required to form adrenaline (epinephrine). Acetylcholine is synthesized from acetyl-Co A and choline by the enzyme choline acetyltransferase (CAT). Choline is made available for this reaction by uptake, via specific high-affinity transporters, within the axonal membrane. Following their synthesis, noradrenaline (norepinephrine) or acetylcholine are stored within vesicles. Release from the vesicle occurs when the incoming nerve impulse causes an influx of calcium ions resulting in exocytosis of the neurotransmitter. 

Figure 14.9 Axonal transport of enzymes, neurotransmitter synthesis, storage in vesicles, release and uptake by presynaptic neurone or enzymic degradation. The neurotransmitter in the synaptic cleft may be removed by the presynaptic neurone (i.e. recycling), by the postsynaptic neurone or by glial cells (not shown). Alternatively, the neurotransmitter may be degraded, and therefore inactivated, by enzyme action. For example, acetylcholine is degraded by acetylcholinesterase in the synaptic cleft (Chapter 3). One of the products, choline, is transported back into the neurone to be reacted with acetyl-CoA to re-form acetylcholine. The vesicle, once empty, may also be recycled for re-packaging (Figure 14.8).

The neuropeptides and hormones mentioned are now formed by limited proteolysis and stored in vesicles. Release from these vesicles takes place by exocytosis when needed. 

Schematic illustration of a generalized cholinergic junction (not to scale). Choline is transported into the presynaptic nerve terminal by a sodium-dependent choline transporter (CHT). This transporter can be inhibited by hemicholinium drugs. In the cytoplasm, acetylcholine is synthesized from choline and acetyl -A (AcCoA) by the enzyme choline acetyltransferase (ChAT). Acetylcholine is then transported into the storage vesicle by a second carrier, the vesicle-associated transporter (VAT), which can be inhibited by vesamicol. Peptides (P), adenosine triphosphate (ATP), and proteoglycan are also stored in the vesicle. Release of transmitter occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine and cotransmitters into the junctional cleft (see text). This step can he blocked by botulinum toxin. Acetylcholine s action is terminated by metabolism by the enzyme acetylcholinesterase. Receptors on the presynaptic nerve ending modulate transmitter release. SNAPs, synaptosome-associated proteins VAMPs, vesicle-associated membrane proteins.

The acetylcholine vesicle release process is blocked by botulinum toxin through the enzymatic removal of two amino acids from one or more of the fusion proteins. 

The activity of N-type and P/Q-type calcium channels is also regulated by proteins that form part of the synaptic vesicle release machinery (Figure 3). These channel subtypes contain a specific synaptic protein interaction site (termed synprint) in the... 

Jarvis SE, Zamponi GW (2001a) Distinct molecular determinants govern syntaxin lA-mediated inactivation and G-protein inhibition of N-type calcium channels. J Neurosci 21 2939 18 Jarvis SE, Zamponi GW (2001b) Interactions between presynaptic Ca2+ channels, cytoplasmic messengers and proteins of the synaptic vesicle release complex. Trends Pharmacol Sci 22 519-25... 

Jarvis SE, Zamponi GW (2005) Masters or slaves Vesicle release machinery and the regulation of presynaptic calcium channels. Cell Calcium 37 483-8 Jun K, Piedras-Renteria ES, Smith SM, Wheeler DB, Lee SB, Lee TG, Chin H, Adams ME, Scheller RH, Tsien RW, Shin HS (1999) Ablation of P/Q-type Ca(2+) channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the alpha(l A)-subunit. Proc Natl Acad Sci U S A 96 15245-50... 

Fig. 3 Mechanisms involved in the opioid ( r, 8, k, ORLi) and neuropeptide Y (Y2) receptor-mediated inhibition of exocytotic transmitter release. Following activation of the respective receptor and Gi/0 (1), three signal transduction pathways are possible, namely inhibition of voltage-dependent Ca2+ channels (2), opening of K+ channels (3), and a direct inhibitory effect on the vesicle release machinery (4). Glossary — > - leading to => - ion flux => - action potential Vm - membrane potential (+) and mean stimulatory and inhibitory effect, respectively.

Y receptors in the rat spinal cord a direct effect on the vesicle release machinery (step 4 in Figure 3) can be assumed, since agonists inhibited the frequency of the miniature inhibitory or excitatory postsynaptic currents (Moran et al. 2004 italics in Table 3). 

Since the orexin receptors are Gq protein-coupled (Alexander et al. 2006), one may assume that this also holds true for the presynaptic orexin receptor(s), but so far no data are available. Nonetheless, the six studies carried out in central nervous preparations permit some conclusions on the post-G protein mechanisms. In all instances, the orexins increased the frequency of spontaneous inhibitory or excitatory postsynaptic potentials or currents. The results differed, however, with respect to the influence of tetrodotoxin. In the medial and lateral hypothalamus (van den Pol et al. 1998 Li et al. 2002), dorsal vagal complex (Davis et al. 2003), and caudal nucleus tractus solitarii (Smith et al. 2002), orexins increased the frequency of the miniature potentials or currents also in the presence of tetrodotoxin, suggesting that they directly influenced the vesicle release machinery (references in italics in Table 5). On the other hand, in the prefrontal cortex (Lambe and Aghajanian 2003) and lat-erodorsal tegmentum (Burlet et al. 2002), the orexins did not retain their facilitatory effect in the presence of tetrodotoxin, suggesting an effect further upstream e.g., on Ca2+ and/or K+ channels. 

It is also possible, however, that the decreased probability of adrenal vesicle release in sdy mice reflects loss of interaction between dysbindin-1 and its binding partner snapin, which normally boosts the number of LDCVs kept in a readily releasable state (Tian et al., 2005) and enhances efficient, synchronous release of synaptic vesicles (Pan et al., 2009). 

Unique mechanism of acfion as modulator of synapfic vesicle release... 

Historically, the word exosome, (beside designating the multienzyme ribonuclease complex identified in S, cerevisiae), has been used to define different types of vesicles released by cells (Figure 1). We feel it is critical to differentiate between the various kinds of vesicles since their mode of biogenesis could be directly related to their physiologic function and/or to the state of the productive cell. 

ACh is found to be stored within the terminals of motor neurons. Detailed analysis has demonshated that ACh is stored within small packages called synaptic vesicles that are concenhated around active zones on the presynaptic membrane. These active zones have been identified as specialized sites for neurohansmitter containing vesicle release. The enzyme for synthesizing ACh from choline and acetyl-Co A, choline acetyl transferase, is also found within the presynaptic terminal. Choline acetyl transferase is found in the cytoplasm. When ACh is synthesized it is pumped into synaptic vesicles by means of a specific carrier molecule located in the vesicle membrane. Once released, ACh subsequently diffuses across the synapse and activates nicotinic ACh receptors localized on the plasma membrane of the postsynapdc muscle cell producing depolarization of the muscle (see below). 

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