Neurobiochemistry Lecture 42 Lecture Lec 42 Richard D. Howells, PhD MSB E-643 howells@umdnj

1. Neurobiochemistry Lecture 42 LectureLec 42Richard D. Howells, PhDMSB E-643howells@umdnj.edu

3. Neuronal Architecture

4. Depolarization phase due to opening of voltage-gated sodium channels; repolarization phase due to opening of voltage-gated potassium channels.

5. Local anesthetics block voltage-gated sodium channels

6. A Chemical Synapse

7. Calcium-dependent neurotransmitter release

8. Neurotransmitters

9. Synthesis and degradation of acetylcholine acetylcholinesterase Choline and acetate

10. Activation at the neuromuscular junction

11. Nicotinic Acetylcholine Receptor: ligand-gated ion channel (ionotropic receptor)

12. Myasthenia gravis • Prototype human autoimmune disease: antibodies are produced against nicotinic AcCh receptors in muscle • Affects 25,000 people in US • Antibodies interfere with synaptic transmission and causes muscle weakness • Cranial muscles and limb muscles affected • Severity of symptoms varies from day to day giving rise to periods of remission or exacerbation • Muscle weakness is reversed by drugs that inhibit acetylcholinesterase, the enzyme that degrades AcCh; thymectomy also helps • Rare, heritable form of myasthenia exists: not autoimmune, mutations in AcCh signaling genes

13. Myasthenia gravis

14. Muscarinic AcChR: cardiac hyperpolarization following vagal stimulation

16. CatecholamineBiosynthesis * * Tyrosine hydroxylase (TH) activity is positively regulated by phosphorylation via cAMP-dependent protein kinase A (PKA). PKA also phosphorylates CREB in the nucleus which activates the TH gene by binding to a CRE enhancer in its 5’-flanking region.

17. Catecholamine metabolism Eisenhofer et al., Pharmacol. Rev. 56:331-349, 2004

18. Parkinson disease • Common neurological disorder affecting 1 million people in US • Symptoms: paucity of spontaneous movement, tremor at rest, muscle rigidity, shuffling gait, mask-like facial expression, autonomic disturbances, depression, cognitive impairment • Results from degeneration of dopamine neurons in the substantia nigra pars compacta • Oral administration of L-DOPA was found beneficial but effects diminish >5 years

20. Five nuclear genes are known to carry mutations that cause rare inherited forms (<10%) of Parkinson Disease

21. Serotonin Biosynthesisand Metabolism

22. Neurotransmitter transporters • Amphetamine inhibits both vesicle and synaptic reuptake of dopamine and norEpi • Desipramine (tricyclic antidepressant) inhibits norEpi reuptake • Fluoxetine (Prozac, antidepressant inhibits serotonin reuptake) • Cocaine inhibits dopamine and norEpi reuptake

23. Synthesis of GABA • Glutamate acts via ionotropic (Na+, Ca2+) and metabotropic (GPCR) receptors, and is the major excitatory neurotransmitter in human brain- excitotoxicity! • GABA acts via ionotropic (Cl-) and metabotropic (GPCR) receptors, and is the major inhibitory neurotransmitter in human brain

24. Benzodiazepines (like diazepam (Valium), flurazepam) facilitate GABAergic transmission

26. Opiate analgesics: exert their activity by binding to opioid receptors in brain (GPCRs)

27. Affects 7% of people >65 y (5 million in USA) • Classical pathology: neurofibrillary tangles and senile plaques in neocortex and hippocampus • Patients show abnormalities of memory, problem solving, judgement, and behavior • Several genetic risk factors for Alzheimer disease have been identified, all of which cause deposition of A amyloid peptide Characteristics of Alzheimer Disease

28. Proteolytic cleavage of amyloid precursor protein (APP) -Secretase

29. Generation of A amyloid peptide: causative agent of Alzheimer Disease? *Evidence suggests presenilins are tightly linked to -secretase-mediated cleavage and play an important role in amyloid precursor protein (APP) cleavage.

30. Neuropathy of Alzheimer Disease Hyperphosphorylated tau protein