Abstract
Butyrylcholinesterase (BChE), a plasma enzyme that hydrolyses the neurotransmitter, acetylcholine relatively well, with far lower efficiency than acetylcholinesterase (AChE) but with the capability to degrade a broad range of bioactive esters. AChE is universally understood as essential to cholinergic neurotransmission, voluntary muscle performance, and cognition, among other roles, and its catalytic impact is essential for life. A total absence of BChE activity, whether by enzyme inhibition or simple lack of enzyme protein is not only compatible with life, but does not lead to obvious physiologic disturbance. However, very recent studies at Mayo Clinic have amassed support for the concept that BChE does have a true physiological role as a “ghrelin hydrolase” and, pharmacologically, as a cocaine hydrolase. Human subjects and animal mutations that lack functional BChE show higher than normal levels of ghrelin, an acylated peptide that drives hunger and feeding, along with certain emotional behaviors. Mice treated by viral gene transfer of BChE show higher plasma levels of enzyme and lower levels of ghrelin. Ghrelin is acknowledged as a driver of food-seeking and stress. This brief review examines some key phenomena and considers means of modulating BChE as treatments for cocaine addiction, anxiety, aggression, and obesity.
Highlights
This brief review focuses on unexpected discoveries in our laboratory during long-term manipulation of plasma butyrylcholinesterase (BChE) by viral gene transfer for multiple purposes
That blood-borne enzyme, nearly universal in higher vertebrates, was first identified as a cholinesterase 70 years ago by Augustinsson who established its ability to hydrolyze acetylcholine (Augustinsson, 1948). This activity was deemed physiologically irrelevant because it was soon recognized that individuals who entirely lack BChE show no discernable disability (Manoharan et al, 2007), presenting a dramatic contrast with acetylcholinesterase, which is essential to life
In the course of time it became clear that BChE was efficient in hydrolyzing certain other bioactive esters, including butyrylcholine and succinylcholine
Summary
This brief review focuses on unexpected discoveries in our laboratory during long-term manipulation of plasma butyrylcholinesterase (BChE) by viral gene transfer for multiple purposes. This state of affairs persisted until our own research encountered unexpected results while pursuing rodent studies on the toxicity and safety of BChE gene transfer as a potential therapy for cocaine abuse. This feature encouraged exploration of treatments for cocaine addiction and overdose, by raising BChE blood levels and enhancing its efficiency by modifying key residues in and around the enzyme’s catalytic site.
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