Protein phosphorylation opiates

The study of protein phosphorylation has helped to clarify the mechanisms involved in the causes and manifestation of disorders of the nervous system. Two illustrative examples are given here Alzheimer s disease and opiate addiction. 

Upregulation of the cAMP pathway may be a common mechanism by which a number of neuronal cell types respond to chronic opiates and develop tolerance and dependence (see Ch. 56). There is also evidence that similar mechanisms involving alterations in the cAMP second-messenger and protein phosphorylation pathway may mediate aspects of addiction to other types of drugs of abuse, for example, cocaine and alcohol [66],... 

Since they are linked to G-proteins, opioid receptors affect intracellular Ca and protein phosphorylation. Another principal biochemical effect of opiates is the inhibition of adenylate cyclase (AC), which decreases cAMP production. 

Synaptic membrane-bound protein kinase activity is regulated by both cAMP and Ca + (106,107). Opiates might thus alter protein kinase activity by reducing Ca + availability, either directly or indirectly via adenylate cyclase. Enzyme induced protein phosphorylation is reported to cause altered membrane ion permeability and thus changes in neuronal excitability. Direct opiate effects on the enzyme could thus produce changes in Ca + distribution such as those discussed previously. 

Chronic opiate treatment results in complex adaptations in opioid receptor signaling. Much has been learned from studies on mechanisms of tolerance to the analgesic effects of opiates. This is a major clinical problem, as it means that ever-escalating doses are required for the treatment of chronic pain. The classic view was that tolerance reflects a decrease in functional opioid receptors via desensitization and internalization. Desensitization occurs when receptors are uncoupled from G proteins as a result of phosphorylation by G-protein-coupled receptor... 

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