Reduced acetylcholine receptor density, morphological remodeling, and butyrylcholinesterase activity can sustain muscle function in acetylcholinesterase knockout mice.
Nerve-evoked contractions were studied in vitro in phrenic nerve-hemidiaphragm preparations from strain 129X1 acetylcholinesterase knockout (AChE-/-) mice and their wild-type littermates (AChE+/+). The AChE-/- mice fail to express AChE but have normal levels of butyrylcholinesterase (BChE) and can survive into adulthood. Twitch tensions elicited in diaphragms of AChE-/- mice by single supramaximal stimuli had larger amplitudes and slower rise and decay times than did those in wild-type animals. In AChE-/- preparations, repetitive stimulation at frequencies of 20 and 50 Hz and at 200 and 400 Hz produced decremental muscle tensions; however, stimulation at 70 and 100 Hz resulted in little or no loss of tension during trains. Muscles from AChE+/+ mice maintained tension at all frequencies examined but exhibited tetanic fade after exposure to the selective AChE inhibitor 1,5-bis(4-allyldimethyl-ammoniumphenyl)pentane-3-one (BW 284C51). The ability of diaphragm muscles from AChE-/- mice to maintain tension at 70 and 100 Hz suggests a partial compensation for impairment of acetylcholine (ACh) hydrolysis. Three mechanisms--including a reliance on BChE activity for termination of ACh action, downregulation of nicotinic acetylcholine receptors (nAChRs), and morphological remodeling of the endplate region--were identified. Studies of neuromuscular transmission in this model system provide an excellent opportunity to evaluate the role of AChE without complications arising from use of inhibitors.
Adler
Michael
M
Neurotoxicology Branch, Pharmacology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010, USA. Michael.Adler@amedd.army.mil
Manley
Heather A
HA
Purcell
Angela L
AL
Deshpande
Sharad S
SS
Hamilton
Tracey A
TA
Kan
Robert K
RK
Oyler
George
G
Lockridge
Oksana
O
Duysen
Ellen G
EG
Sheridan
Robert E
RE
D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D002093:Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000378:metabolism* / Q000502:physiology; D003964:Diaphragm / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D006868:Hydrolysis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000378:metabolism* / Q000648:ultrastructure
D011978:Receptors, Nicotinic; D002093:Benzenaminium, 4,4'-(3-oxo-1,5-pentanediyl)bis(N,N-dimethyl-N-2-propenyl-), Dibromide; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D000109:Acetylcholine