Probability of Neurotransmitter Release

Abstract Modulation of neurotransmitter release by G-protein-coupled receptors (GPCRs) is a prominent presynaptic mechanism for regulation of synaptic transmission. Activation of GPCRs located at the presynaptic terminal can decrease the probability of neurotransmitter release. This presynaptic depression involves activation... 

Choi S, Lovinger DM (1997a) Decreased probability of neurotransmitter release underlies striatal long-term depression and postnatal development of corticostriatal synapses. Proc Natl Acad... 

These approaches are, in any case, only suitable for classical neurotransmitters. Those with slow background effects will probably not be released in large amounts. For such substances we require a measure of their utilisation, or turnover, over a much longer period of time. With NTs released from short-axon interneurons there are no pathways to stimulate and it becomes necessary to activate the neurons intrinsically by field stimulation, which is of necessity not specific to the terminals of the interneurons. 

G0 was isolated as an other PTx-ribosylated G-protein which co-purifies with G, but which does not inhibit adenylate cyclase. There are two main isoforms (G0l and Go2), with additional splice-variants. G0 is particularly abundant in the nervous system, comprising up to 1% of membrane proteins. Its main function is to reduce the opening probability of those voltage-gated Ca2+ channels (N- and P/Q-type) involved in neurotransmitter release. Hence, it is largely responsible for the widespread auto-inhibition of transmitter secretion by presynaptic receptors and this effect is mediated through released py subunits. 

As indicated above, detection of evoked quantal responses (either through minimal stimulation or paired recordings) provides a suitable setting to determine neurotransmitter release probability and alterations in rate of vesicle fusion. However, in synapses with multiple release sites, such as the calyx of Held, isolation of evoked quantal responses is nearly impossible and truly quantal release is hard to detect except in the case of spontaneous neurotransmission. Therefore, under these conditions, the rate of synaptic vesicle fusion can be determined by deconvolution of synaptic currents with the quantal unitary current. This approach is valid only when the synaptic current can be assumed to result from the convolution between a quantal current and quantal release rates. This assumption is not valid in cases where post-synaptic mechanisms, such as receptor saturation and desensitization, alter quantal events and thus shape synaptic responses during repetitive stimulation (Neher and Sakaba, 2001). 

Fig. 4 Stages in synaptic vesicle exocytosis. Putative intermediate steps on the molecular pathway to synaptic vesicle fusion. Vesicle delivery and tethering to the presynaptic membrane most likely involves Rab-proteins and their effectors. So far, the nature of a speculative docking complex (dc) is unclear, but docking appears to be independent from SNARE proteins. In the primed state, SNAREs have assembled into a complex probably stabilized by complexin (Cpx). The fusion reaction is arrested until the intracellular calcium concentration increases. The putative calcium sensor for fast neurotransmitter release, synaptotagmin 1 (Syt), binds to intracellular calcium and in turn triggers fusion by associating with the presynaptic membrane and interacting with the SNARE complex, thereby displacing complexin (Tang et al. 2006).

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