In its simplest form, the postsynaptic response to neurotransmitter release can be mediated by a single protein complex. For example, nicotinic acetylcholine receptors are self-contained stimulus-response modules that both detect a stimulus, acetylcholine, and generate a response, passage of ion currents. In a similar vein, other members of this superfamily of ionotropic receptors, including g-aminobutyric acid (GABA) and glutamate receptors, have the ability to function in a manner that is independent of the intracellular signaling pathways discussed. Thus, in contrast to growth factor or G-protein–coupled receptors, which often recruit elaborate cascades to elicit a response, the simplicity of self-sufficient ionotropic receptor complexes represents an optimal design for achieving reliability, precision, and speed. However, this view of ionotropic receptors as insulated from their social environment has had to be abandoned in the face of overwhelming evidence that this class of receptors is dynamically regulated by intraneuronal signaling pathways. Although these receptors do not rely on intraneuronal signaling pathways to operate ion channels, because these channels are an intrinsic feature of the receptor complex the linkage between ligand binding and ion channel gating is nevertheless subject to regulation by the network of intraneuronal signaling pathways just described. For example, phosphorylation of the GABA or glutamate receptors modulates their response to ligand exposure.
[...] Role of Phosphorylation The associative property of this model of synaptic plasticity has focused attention on deciphering the intraneuronal signaling pathways that mediate the long-term change in synaptic transmission triggered by NMDA receptor stimulation. NMDA receptor activation leads to transient rises in intracellular levels of calcium making this second messenger an attractive candidate. Experiments demonstrating that intracellular calcium chelators block this form of long-term potentiation corroborated the critical role of calcium in this process. Subsequent studies investigated whether either of the calcium-sensitive kinases that are highly enriched in neuronal dendrites, calcium/calmodulin-dependent kinase II and protein kinase were critical for this process. [...]
[...] Although the formal similarities between the associative properties of long- term potentiation and classical conditioning have provided compelling support for the hypothesis that this form of synaptic plasticity underlies associative learning, it has been difficult to gain experimental support linking this electrophysiological response to the behavioral phenomena. An important breakthrough in this area has been the utilization of transgenic animals with targeted mutations in genes encoding signaling molecules involved in long-term potentiation. The ability to examine the effect of these genetic alterations on behavior in the intact animal as well as on long-term potentiation in vitro has provided a means of bridging the gap between intraneuronal signaling pathways and behavior. [...]
[...] In the specific example of long-term depression in cerebellar Purkinje cells, the plasticity observed is triggered by coordinate activation of two distinct classes of afferents to these neurons. Purkinje cells receive a major input from both climbing fibers arising from the inferior olive and parallel fibers that emanate from granule cells of the cerebellum. The parallel-fiber response in an individual Purkinje cell is decreased if that cell is coincidentally activated by a climbing fiber input. Analysis of this phenomenon has revealed that it is dependent on coincident activation of two distinct types of glutamate receptors: an a-amino-3-hydroxyl methyl-4-isoxazole propionic acid (AMPA) type of ionotropic glutamate receptors and a G-protein–coupled (metabotropic) glutamate receptor that linked to the PI system. [...]
[...] Role of NMDA Receptor Activation Prior to outlining the intracellular signaling pathways involved in long-term potentiation, it is first important to understand the key synaptic events that trigger plasticity in this paradigm. Studies of long-term potentiation of inputs to CA1 hippocampal neurons have highlighted the role of N-methyl-D-aspartate (NMDA) receptors as coincidence detectors. In this system basal levels of synaptic activity are mediated by activation of AMPA receptors. Even though the same synapses also express NMDA receptors, under quiescent conditions these do not open in response to glutamate because NMDA receptors have an additional requirement that must be met before they open. [...]
[...] According to this theory, the intracellular signaling pathway regulating the responsiveness of presynaptic receptors is the critical determinant of the antidepressant response. Another example is provided by recent studies implicating the cAMP system in mediating responses elicited by long-term opiate administration. Many of the acute effects of opiate receptor activation on ion channel function are mediated directly by Gi proteins, independent of cAMP. However, in parallel with these electrophysiological effects, opioid receptor activation also suppresses cAMP concentrations. With long-term administration of opioids, neurons adapt to this persistent suppression of cAMP concentrations by altering the expression of several components of the cAMP system, yielding a net increase in cAMP tone to compensate for the chronic negative influence of opioids. [...]
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