Readthrough acetylcholinesterase: a multifaceted inducer of stress reactions

Stress insults induce hyperexcitation of cholinergic circuits, both peripherally in the sympathetic pathway (Tracey, 2002) and at the central nervous system (CNS) (Sapolsky, 1996). This reaction can serve to ensure survival but might also entail a risk to the hyperactivated neurons. Consequent changes in the expression of a series of proteins related to acetylcholine (ACh) metabolism might protect the organism from the potentially detrimental effects of this increase in ACh. Of particular interest among these effects is the induction by alternative splicing of the alternative, usually rare, readthrough variant of acetylcholinesterase (AChE), AChE-R. AChE-R is one of the first proteins conveying the signal that the organism has entered a state of alert. Viewing AChER as a stress signal can therefore serve to answer the question "How do we expect a stress signal to operate"? This facilitates the generation of hypotheses regarding the triggering of such signals and the effects it exerts at the molecular, cellular, and physiological levels.