Eric Niederhoffer SIU-SOM

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Presentation transcript:

Eric Niederhoffer SIU-SOM 12/3/2017 Acetylcholine Synthesis and degradation Receptors Neuromuscular junction disorders Eric Niederhoffer SIU-SOM

Acetylcholine Synthesis and Degradation 12/3/2017 Acetylcholine Synthesis and Degradation Pyruvate PDH complex (FAD, lipoamide, TPP) Acetyl-CoA + choline Reuptake or diet Acetylcholine Choline acetyltransferase (CAT) (inhibited by mercurials) Acetylcholinesterase (AChE) (membrane associated; inhibited by nerve agents, sarin) Acetate + choline PDH: pyruvate dehydrogenase FAD: flavin adenine dinucleotide TPP: thiamine pyrophosphate (vitamin B1) AChE: acetylcholinesterase Choline may be obtained from eggs, liver, beef steak, soy (lecithin = phosphatidyl choline) CAT deficiency found in Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), schizophrenia

Acetylcholine Receptor 12/3/2017 Acetylcholine Receptor AChR a b ACh g (or e) ACh d a ACh: acetylcholine AChR: acetylcholine receptor is the nicotinic hetero(and penta)meric muscle form, which has (a1)2,b,g,d fetal subunit composition and (a1)2,b,e,d adult subunit composition Miyazawa, A., Y. Fujiyoshi, and N. Unwin. 2003. Structure and gating mechanism of the acetylcholine receptor pore. Nature 423:949-955.

Acetylcholine Receptor 12/3/2017 Acetylcholine Receptor http://www.neuro.wustl.edu/neuromuscular/mother/acetylcholine.htm For the muscle nicotinic AChR (nAChR), PCa2+/PNa+ = 0.2-1. These are heteromeric receptors with respect to subunit composition. For neuronal nAChR, PCa2+/PNa+ = 6-20. These are either heteromeric or homomeric receptors with respect to subunit composition. Muscarinic AChR (mAChR, type M1, M2, M3, M4,or M5) operate through G protein signal pathways. nAChR - ionotropic; mAChR - metabotropic http://www.med.upenn.edu/ins/faculty/lindstro.htm Jon M. Lindstrom, Dept Neuroscience School of Medicine, University of Pennsylvania

Neuromuscular Junction Disorders 12/3/2017 Neuromuscular Junction Disorders http://www.neuro.wustl.edu/neuromuscular/synmg.html Myasthenia Gravis autoimmune IgG against a1 subunit (muscle nAChR) Inherited disorders with a, b, d, or e subunits (muscle nAChR) Variety of disorders with neuronal nAChR Kinetic problems with channels IgG against M3 (mAChR) AChE deficiency nAChR: nicotinic acetylcholine receptor mAChR: muscarinic acetylcholine receptor AChE: acetylcholinesterase For disorders, consider synthesis of ACh and AChR, release of ACh, binding of ACh and AChR, and degradation of ACh by AChE.

12/3/2017 Review Questions How is ACh synthesized (substrates, enzyme, coenzyme)? How is ACh degraded (products, enzyme, location)? What are the composition and characteristics of AChR? How does ACh interact with AChR (binding sites)? What are the common disorders associated with ACh, AChE, and AChR?