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.
Neurotoxicology Branch, Pharmacology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010, USA. Michael.Adler@amedd.army.mil
Michael
M
Adler
Heather A
HA
Manley
Angela L
AL
Purcell
Sharad S
SS
Deshpande
Tracey A
TA
Hamilton
Robert K
RK
Kan
George
G
Oyler
Oksana
O
Lockridge
Ellen G
EG
Duysen
Robert E
RE
Sheridan
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