Anticholinesterase drugs, including insecticides and chemical warfare agents, as well as some therapeutic drugs used for myasthenia gravis treatment, interfere with acetylcholinesterase. This interference prolongs the presence of acetylcholine at its synapses and enhances its action. In myasthenia gravis, an autoimmune disease, antibodies bind to acetylcholine receptors at the neuromuscular junction, disrupting their functionality and causing rapid degradation. This reduction in receptors leads to severe weakness and paralysis, characterized by rapid muscle tiring with repeated use. The decrease in release of acetylcholine with repeated activity in people with myasthenia gravis fails to trigger spikes, resulting in muscle contraction failure. Standard treatments for myasthenia gravis include anticholinesterases, which partially overcome the deficit caused by the reduced number of functional postsynaptic receptors. Immunosuppressive therapies and plasma exchange are also used to reduce autoantibody levels against the acetylcholine receptor, but these therapies have many side effects due to their nonspecific nature. Potential future therapies aim to induce tolerance to the acetylcholine receptor and selectively destroy the B cells that produce antibodies against the receptor.

Acetylcholine synthesis occurs from acetyl coenzyme A and choline, catalyzed by the enzyme choline acetyltransferase. This enzyme is located in the cytoplasm of cholinergic presynaptic terminals. Acetylcholine is then concentrated in vesicles before its release. Acetylcholinesterase, highly concentrated in the synaptic cleft, terminates the action of acetylcholine by hydrolyzing it into acetate and choline. Choline is subsequently taken up by a Na+ symporter in the presynaptic membrane to resynthesize acetylcholine. Unlike other classic neurotransmitters, acetylcholine undergoes extracellular enzymatic degradation instead of reuptake by specialized transporter proteins.

Fig. 6.11 illustrates the glutamate transport cycle. Glutamate, a neurotransmitter, is released from a presynaptic terminal. Distinct glutamate transporters exist on the presynaptic and postsynaptic cell membranes for its reuptake. Additionally, glial cells uptake glutamate and convert it to glutamine. Glutamine is then released and taken into the presynaptic terminal, where it is converted back to glutamate before being repackaged into synaptic vesicles. The transporters facilitate the ion flow associated with the movement of glutamate across the membrane.

Neurotransmitters can be various amino acids, with the three most important being glutamate, glycine, and GABA.
Anumberofdrugsknownasanticholinesterases interferewithacetylcholinesteraseandtherebyenhancetheactionofacetylcholinebyprolongingitspresenceatitssynapses.Suchdrugsincludeinsecticidesandchemicalwarfareagents,aswellassometherapeuticdrugs,suchasthoseusedtotreatmyasthenia gravis. Myastheniagravisisanautoimmunediseaseinwhichantibodiesbindtoacetylcholinereceptorsattheneuromuscularjunction,therebydisruptingtheirfunctionalityandcausingthemtobemorerapidlydegraded.Thisreductioninreceptorsleadstosevereweaknessandultimatelyparalysis.Theweaknessischaracterizedbyrapidtiringofthemusclewithrepeateduse.Rapidtiringoccursbecausethenumberofpresynapticvesiclesavailableforreleasedropsduringthehigh-frequencytrainofmotorneuronactionpotentialsthatgeneratessuchcontractions.Normally,becauseofthehighsafetyfactoroftheneuromuscularjunction,smallerbutstillsuprathresholdEPPswouldstillbegeneratedandmaintainmusclecontractionduringrepeateduse.Inpeoplewithmyastheniagravis,thesafetyfactorissoreducedbythelossofacetylcholinereceptorsthatthedecreaseinreleaseofacetylcholinewithrepeatedactivityleadstoEPPsthatfailtotriggerspikes,andthusmuscularcontractionfails.Standardtreatmentsincludeanticholinesterases,whichallowagreaterconcentrationofacetylcholinetopartiallyovercomethedeficitcausedbythereducednumberoffunctionalpostsynapticreceptors,andimmunosuppressivetherapiesandplasmaexchange,whichreducelevelsofautoantibodiesagainsttheacetylcholinereceptor.Thesetherapiesareallrelativelynonspecificandcanthereforehavemanysideeffects.PotentialfuturetherapiesarebeingdevelopedandincludeinducingtolerancetotheacetylcholinereceptorandselectivedestructionoftheBcellsthatmakeantibodiesagainstthereceptor.
Acetylcholine is synthesized from acetyl coenzyme A and choline by the enzyme choline acetyltransferase, which is located in the cytoplasm of cholinergic presynaptic terminals. After synthesis, acetylcholine is concentrated in vesicles. After release, the action of acetylcholine is terminated by the enzyme acetylcholinesterase, which is highly concentrated in the synaptic cleft. Acetylcholinesterase hydrolyzes acetylcholine into acetate and choline. The choline is then taken up by an Na+ symporter in the presynaptic membrane for the resynthesis of acetylcholine. The extracellular enzymatic degradation of acetylcholine is unusual for a neurotransmitter inasmuch as the synaptic action of other classic neurotransmitters is terminated via reuptake by a series of specialized transporter proteins.
•Fig. 6.11 Glutamatetransportcycle.A, Schematicshowsthefateofglutamatereleasedfromapresynapticterminal.Distinctglutamatetransportersexistonthepresynapticandpostsynapticcellmembranesforreuptake.Inaddition,glialcellstakeupglutamateandconvertittoglutamine.Theglutamineisthenreleasedandtakenintothepresynapticterminal,whereitisconvertedbacktoglutamatebeforebeingrepackagedintosynapticvesicles.B, Schematicoftransportershowingdirectionofionflowassociatedwiththemovementofglutamateacrossthemembrane.
A variety of amino acids function as neurotransmitters. The three most important are glutamate, glycine, and GABA.