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Pathways of Addiction: Opportunities in Drug Abuse Research
neurotransmitters or interact with their G proteins. Phosphorylation of enzymes affects their catalytic activity (e.g., phosphorylation of adenylyl cyclase can increase its capacity to synthesize cAMP).
The brain contains many types of protein kinases and protein phosphatases that exhibit differential regulation. For example, cAMP activates cAMP-dependent protein kinases, Ca2+ activates Ca2+-dependent protein kinases, etc. Each type of protein kinase then phosphorylates a specific array of target proteins and thereby produces many additional effects of the original neurotransmitter-G protein-second messenger stimulus.
Due to the multiple effects of phosphorylation on a number of important intracellular processes, a neurotransmitter stimulus can influence virtually every chemical process that occurs within its target neurons. Some effects, such as alterations in electrical activity, are very rapid (within seconds) and short-lived. Other effects, such as alterations in gene expression, can develop more slowly (over minutes or hours) and last for a long time. These more long-lasting effects of a neurotransmitter stimulus alter the manner in which the target neuron responds to subsequent stimuli—both the original neurotransmitter and others—and presumably represent the basis of neural adaptation and change, called plasticity. Together, these types of responses of widely differing time courses allow neurons to exert very complex control over other neurons operating within neural circuits.
Neurotrophic Factor Signaling Pathways
Second-messenger–regulated protein phosphorylation is just one component of a neuron's complex intracellular regulatory mechanisms. Neurons contain many protein kinases and protein phosphatases in addition to those regulated by second messengers, and these enzymes also contribute to the diverse effects that a neurotransmitter stimulus exerts on its target neurons. For example, neurotrophic factors were first studied for their important role in neural development and differentiation. However, it is now known that neurotrophic factors also play an important role in the regulation of the fully differentiated adult brain. One important family of neurotrophic factors, called neurotrophins, binds to a class of receptor that contains a special type of protein kinase within its structure, a protein tyrosine kinase, which phosphorylates proteins specifically on tyrosine residues. Binding of neurotrophin to its protein tyrosine kinase receptor activates the kinase activity and leads to the phosphorylation of specific cellular proteins and, eventually, to a cascade of protein kinase activity. Thus, neurotrophic factor-related signaling pathways are another example of the complexity of a neuron's intracellular regulatory machinery, and serve to highlight the complex types of effects that a