Extrasynaptic Receptors

Extrapyramidal Side Effects Extrasynaptic Receptors F-actin... 

The reuptake process does not capture all of the released catecholamine. Diffusion away from the nerve terminal to distant sites can occur and has been termed volume transmission [23]. Volume transmission allows the stimulation of extrasynaptic receptors, which has been described for dopamine [24] and norepinephrine [25]. Brain regions differ in their capacity for catecholamine reuptake thus, whereas extracellular dopamine concentrations are dominated by release in the cerebral cortex, in the striatum dopamine concentrations are dominated by reuptake [26]. These regional differences in extracellular dopamine kinetics correlate with levels of dopamine transporter [27]. 

Ebert, B., Storustovu, S., Mortensen, M., and Frplund, B. (2002) Characterization of GABA(A) receptor ligands in the rat cortical wedge preparation evidence for action at extrasynaptic receptors Br. J. Pharmacol. 137,1-8. 

The dynamics of the release and uptake of dopamine into brain extracellular space are currently under intense investigation[20-22]. Dopamine is a well-known extrasynaptic messenger that functions via volume transmission, escaping from the synaptic cleft to bind to extrasynaptic receptors and transporters. High sensitivity, chemical selectivity, and fast temporal resolution are all desirable characteristics in detecting neurotransmitters in vivo. In practice, it is difficult to achieve all of these with one method. 

Functional and immunocytochemical studies have shown that NMDARs are present at both synaptic and extrasynaptic sites. It is possible that the extrasynaptic population simply represents receptors that have been delivered to the plasma membrane and are awaiting incorporation into the synapse. This idea is supported by recent work that shows that NMDARs can rapidly move between synaptic and extrasynaptic sites, possibly by lateral diffusion of the receptors (81). However, the possibility remains that there is a distinct population of extrasynaptic receptors with a specific function. Extrasynaptic receptors respond differently to excitotoxic drugs (82) and may be activated under physiological conditions (83). There is also evidence of a selective coupling of NMDA channels at extrasynaptic sites to inhibitory currents, which may limit excitation during periods of intense activity (84). 

Synaptic and extrasynaptic receptors may also differ in their subunit compositions. The kinetics of NMDA excitatory postsynaptic currents (EPSCs) become faster during development in the CNS and correlate with an increase in expression... 

ACh is the best established transmitter candidate in nematodes. It was first isolated from A. suum (113). Microiontophoresis of ACh onto the ends of muscle arms at the nerve cords of A. suum produces depolarizations that can be blocked by 4-tubocurarine and potentiated by AChE inhibitors (114). In addition to the ACh receptors at the nerve cords, muscles also have extrasynaptic receptors (115-117). Biochemical assays show that the excitatory motoneurons contain ChAT whereas the inhibitory motoneurons do not (118). Stimulation of the excitors leads to muscle cell depolarization which is blocked by d-tubocurarine (119). 

Extrasynaptic receptors in the supportive glial cells of the CNS are responsible for the uptake (synaptic gap clearance) and transport of GABA to terminate the neurotransmission. These receptor sites differ markedly from the GABAyy sites in SAR response to GABA analogs. Other uptake sites within the neuronal structure appear to differ from those in the glial cells according to comparative studies by Schousboe... 

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