Synaptic transmission, phospholipase

Interest in the PGs has recently reverted to their precursor arachidonic acid (AA), which seems to be able to act intracellulary as a second messenger, and also extra-cellularly. In this latter mode it may play a part in LTP. It is known that AA produces a long-lasting enhancement of synaptic transmission in the hippocampus that resembles LTP and in fact activation of NMDA receptors leads to the release of AA by phospholipase A2 (see Dumuis et al. 1988) and inhibition of this enzyme prevents the induction of LTP. AA has also been shown to block the uptake of glutamate (see Williams and Bliss 1989) which would potentiate its effects on NMDA receptors. This would not only prolong LTP but also cause neurotoxicity. 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

St-Gelais F., Menard C., Congar P., Tmdeau L. E., and Massicotte G. (2004). Postsynaptic injection of calcium-independent phospholipase A2 inhibitors selectively increases AMPA receptor-mediated synaptic transmission. Hippocampus 14 319-325. 

Figure 29-2. Postulated effect of lithium on the IP3 and DAG second messenger system. The schematic diagram shows the synaptic membrane of a neuron in the brain. PLC, phospholipase-C G, coupling protein R. receptor PI, PIP, PIP, IP, IP, intermediates in the production of IP3. By interfering with this cycle, lithium may cause a use-dependent reduction of synaptic transmission. (Modified and reproduced, with permission, from Katzung BG [editor] Basic Clinical Pharmacology, 8th ed. McGraw-Hill, 2001.)...

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