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E.M. Silinsky Ward 7-245 Tel: 503-8287 e-mail: e-silinsky@northwestern

E.M. Silinsky Ward 7-245 Tel: 503-8287 e-mail: e-silinsky@northwestern.edu. Signal Transduction and Receptor Pharmacology in the Peripheral Nervous System (PNS ): a Primer for the Cardiovascular , Pulmonary, Renal and Musculoskeletal ( MSK) Modules. I. GENERAL OVERVIEW.

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E.M. Silinsky Ward 7-245 Tel: 503-8287 e-mail: e-silinsky@northwestern

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  1. E.M. Silinsky Ward 7-245 Tel: 503-8287 e-mail: e-silinsky@northwestern.edu Signal Transduction and Receptor Pharmacology in the Peripheral Nervous System (PNS):a Primer for theCardiovascular, Pulmonary, Renal and Musculoskeletal (MSK)Modules

  2. I. GENERAL OVERVIEW Peripheral Nervous System (PNS) • SOMATIC Nervous System (Voluntary) • AUTONOMIC Nervous System) (Involuntary) Sympathetic division-flight/fight Parasympathetic division-rest and digest

  3. GPCRs ANS ANS SOMATIC N LIGAND-GATED CHANNEL M – muscarinic N - nicotinic Nor –norepinephrine (NE) α and β - adrenoreceptors Ach - Acetylcholine

  4. PHARMACODYNAMICS=RECEPTORSOVERVIEW and LINKAGES TO OTHER LECTURES SIGNAL TRANSDUCTION after receptor binding occurs with varying degrees of RAPIDITY In this lecture, we will only consider these SIGNAL TRANSDUCTION processes d d Transmembrane enzymes (tyrosine kinases) Ligand-gated ion channel G-proteins coupled receptors (GPCRs) Nuclear Receptors (Transcriptional regulators)

  5. GPCRs ANS ANS SOMATIC N LIGAND-GATED CHANNEL We begin with the SOMATIC Division

  6. II. The Somatic Nervous System SKELETAL NEUROMUSCULAR JUNCTION (NMJ) SPINAL CORD From Dr. Cochard: Somatomotor fiber to skeletal muscle: SPINAL CORD THE LIGAND-GATED ION CHANNEL (NICOTINIC RECEPTOR) <1/3 of a millisecond from binding to response.

  7. COMPUTER AMP NERVE MUSCLE THE ELECTROPHYSIOLOGIST’S APPROACH TO SKELETAL NEUROMUSCULAR TRANSMISSION

  8. INTRACELLULAR RECORDING MICROELECTRODE AT INNERVATED REGION OF MUSCLE COMPUTER AMP NERVE -70 mV MUSCLE -70mv (Vm) THE ELECTROPHYSIOLOGIST’S APPROACH TO SKELETAL NEUROMUSCULAR TRANSMISSION

  9. NERVE STIMULUS COMPUTER AP in nerve 3 ms ELECTRICAL EVENTS IN MUSCLE IN RESPONSE TO NERVE STIMULUS Could this be a direct transfer of electrical information from nerve to muscle?

  10. NOT! Motor nerve endings are too small for electrical synaptic transmission! Instead, the electrical events recorded in the muscle in response to nerve stimulation are due to the release of acetylcholine (ACh) contained within synaptic vesicles in the motor nerve ending. ACh synaptic vesicle

  11. NERVE STIMULUS EPP Produced by acetylcholine release from nerve endings acting on nicotinic receptors and called end-plate potentials (EPPS)

  12. NERVE STIMULUS MAP End-plate potential (EPP) NORMALLY an EPP produces a muscle action potentials (MAP) and a muscle twitch

  13. myelin From Lester, H. (1979) Scientific American vesicles Calcium channels Synaptic vesicles Active zone Nicotinic AChR acetylcholinesterase Muscle

  14. NERVE TERMINAL ACh S1 vesicle This vesicle cannot release ACh in membrane Ca channel out NICOTINIC RECEPTORS SKELETAL MUSCLE

  15. NERVE TERMINAL ACh vesicle S1 To be releasable, vesicles must be primed or 'SNARED' FUSION brevin tagmin MACHINE in S-25 membrane exin taxin Ca channel out NICOTINIC RECEPTORS SKELETAL MUSCLE

  16. THE FUSION MACHINE ●THE SNARES-prime the secretory apparatus i.e. make the nerve terminal fusion competent) (Three intertwined nerve terminal proteins that link the vesicles to the plasma membrane near calcium channels). ● A CALCIUM SENSOR-This is a vesicular protein that binds calcium It is wrapped around the SNAREs. It is called synaptotagmin. .

  17. NERVE TERMINAL ACh vesicle S1 1 3b 3a SECRETION 2 FUSION brevin tagmin ACTION MACHINE POTENTIAL (AP) Ca entry S-25 membrane exin membrane taxin choline OPENED BY ACTION POTENTIAL Ca channel Ca AP CLEFT AChE ACh 5 NICOTINIC RECEPTORS 4 EPP Na+ hydrolysis Na+ Na+ Na+ SKELETAL MUSCLE K+ microelectrode

  18. At this juncture, an animation will be presented in class. Please see the slides beginning at # 101 if you are interested in revisiting the animation.

  19. IMPORTANT AGENTS TO KNOW NERVE TERMINAL ACh vesicle S1 1 3b 3a SECRETION 2 FUSION brevin tagmin ACTION MACHINE POTENTIAL (AP) Ca entry S-25 membrane exin membrane taxin choline OPENED BY ACTION POTENTIAL Ca channel Ca AP CLEFT AChE ACh 5 NICOTINIC RECEPTORS 4 EPP Na+ hydrolysis Na+ Na+ Na+ SKELETAL MUSCLE K+ microelectrode

  20. NERVE TERMINAL ACh vesicle S1 FUSION brevin tagmin MACHINE Ca entry S-25 membrane exin membrane taxin OPENED BY ACTION POTENTIAL Ca channel Ca 2 ACTION POTENTIAL (AP) Tetrodotoxin (TTX) blocks Na+ channel involved in upstroke of AP

  21. NERVE TERMINAL ACh vesicle S1 1 TTX blocks AP Na+ channel 3b 3a SECRETION 2 FUSION brevin tagmin ACTION MACHINE POTENTIAL (AP) Ca entry S-25 membrane exin membrane taxin TTX blocks AP Na+ channel only OPENED BY ACTION POTENTIAL Ca channel Ca AP CLEFT ACh NICOTINIC RECEPTORS 4 EPP Na+ Na+ Na+ Na+ SKELETAL MUSCLE K+ microelectrode

  22. Chicago Tribune, July 2008 TTX The owner of this home was caught in an FBI sting. He posed as a physician to order TTX to commit a dastardly deed.

  23. NERVE TERMINAL ACh vesicle S1 1 TTX blocks AP Na+ channel 3b 3a SECRETION 2 FUSION brevin tagmin ACTION MACHINE POTENTIAL (AP) Ca entry S-25 membrane exin membrane taxin TTX blocks AP Na+ channel only OPENED BY ACTION POTENTIAL Ca channel Ca AP CLEFT ACh NICOTINIC RECEPTORS 4 EPP Na+ Na+ Na+ Na+ SKELETAL MUSCLE K+ microelectrode

  24. NERVE TERMINAL ACh vesicle S1 3a FUSION brevin tagmin Calcium entry: reduced by: MACHINE S-25 membrane exin taxin OPENED BY ACTION POTENTIAL Ca channel Ca ●Mg2+ and other polyvalent cations ●Aminoglycoside antibiotics*

  25. Botulinum toxins block secretion NERVE TERMINAL ACh vesicle S1 1 3b 3a SECRETION 2 FUSION brevin tagmin ACTION MACHINE POTENTIAL (AP) Ca entry S-25 membrane exin membrane taxin choline OPENED BY ACTION POTENTIAL Ca channel Ca AP CLEFT AChE ACh 5 NICOTINIC RECEPTORS 4 EPP Na+ hydrolysis Na+ Na+ Na+ SKELETAL MUSCLE K+ microelectrode

  26. Botulinum toxin type A (BOTOX A) works on ACh SNAP-25 vesicle S1 1 3b 3a SECRETION 2 FUSION brevin tagmin ACTION MACHINE POTENTIAL (AP) Ca entry S-25 membrane exin membrane taxin choline OPENED BY ACTION POTENTIAL Ca channel Ca AP CLEFT AChE ACh 5 NICOTINIC RECEPTORS 4 EPP Na+ hydrolysis Na+ Na+ Na+ SKELETAL MUSCLE K+ microelectrode

  27. BOTOX A ACh SNAP-25 Cleaved SNAP-25 vesicle S1 INHIBITION OF SECRETION 3a FUSION brevin tagmin ACTION MACHINE POTENTIAL (AP) Ca entry S-25 membrane exin membrane taxin OPENED BY ACTION POTENTIAL Ca channel Ca CLEFT NICOTINIC RECEPTORS 4 Na+ hydrolysis Na+ Na+ Na+ SKELETAL MUSCLE K+ microelectrode

  28. BLEPHAROSPASM-intermittent or persistent eye closure produced by spasmodic contractions of the orbicularis oculi muscles

  29. Inject1 ng of BOTOX (botulinum toxin type A) -relief for 90% of patients for 2-4 months ORBICULARIS OCULI MUSCLE

  30. AP ACh NICOTINIC RECEPTORS 4 EPP Na+ Na+ Na+ Na+ K+ microelectrode SKELETAL MUSCLE

  31. SIGNAL TRANSDUCTION AT THE SKELETAL NMJ IS EXCLUSIVELY BY: THE LIGAND-GATED ION CHANNEL ACETYLCHOLINE initiating skeletal muscle contraction NICOTINIC RECEPTOR (a ligand gated ‘sodium’ channel) <1/3 of a millisecond from binding to response.The fastest signal transduction motif in biology!

  32. NON-DEPOLARIZING BLOCK =COMPETITIVE INHIBITION ACh tubocurarine ACh EXCLUDED FROM RECEPTOR BY TUBOCURARINE (curare), the South American Indian arrow poison. SURMOUNTABLE BY INCREASING [ACh]

  33. Site 4-THE NICOTINIC RECEPTOR BLOCKERS ●TUBOCURARINE (CURARE) -The South American Indian arrow poison. The prototype for competitive inhibitors (called non-depolarizing blockers). ●VECURONIUM-One of the most popular non-depolarizing blockers to relax skeletal muscles during surgical procedures. ●SUCCINYLCHOLINE a depolarizing blocker because it depolarizes the muscle before it blocks-used to relax skeletal muscles for intubation.

  34. AP AChE ACh 5 NICOTINIC RECEPTORS 4 EPP Na+ hydrolysis Na+ Na+ Na+ SKELETAL MUSCLE K+ microelectrode

  35. Normal nerve terminal ACh removed by: DIFFUSION HYDROLYSIS ChE INHIBITION ACh removed by: DIFFUSION only [ACh] remains high longer Hydrolysis products Receptors Receptors

  36. SITE 5- CHOLINESTERASE INHIBITORS These drugs inhibit the degradation of ACh, enhancing synaptic transmission when it is impaired by a nicotinic receptor deficit at the skeletal neuromuscular junction. ●NEOSTIGMINE(reversible inhibitor) used to speed recovery from non-depolarizing block and to treat disease in which enhancing cholinergic transmission would be helpful. ●SARIN-(irreversible inhibitor)-nerve gas

  37. TO REVIEW OUR DISCUSSION OF THE NMJ, SIGNAL TRANSDUCTION IS EXCLUSIVELY BY: THE LIGAND-GATED ION CHANNEL ACETYLCHOLINE initiating skeletal muscle contraction NICOTINIC RECEPTOR (a ligand gated ‘sodium’ channel) <1/3 of a millisecond from binding to response.The fastest signal transduction motif in biology! End of the somatic system

  38. GPCRs ANS ANS SOMATIC N

  39. III. The Autonomic Nervous System (ANS) OVERVIEW THE LIGAND-GATED ION CHANNEL 1 2 4 3 SOMATIC 1 3 4 N 2 GPCRs TRANSMITTER SUBSTANCESNATURE OF RECEPTOR M – muscarinic N - nicotinic Nor –norepinephrine (NE) α and β - adrenoreceptors Ach - Acetylcholine

  40. III. The Autonomic Nervous System (ANS) SOMATIC N GPCRs

  41. SIGNAL TRANSDUCTION after receptor binding occurs with varying degrees of RAPIDITY d d Ligand-gated ion channel NICOTINIC RECEPTOR G-proteins coupled receptors (GPCRs)

  42. SYNAPTIC TRANSMISSION IN THE ANS COMPARISONS with the SKELETAL NMJ

  43. PARASYMPATHETIC NERVE TERMINAL ACh vesicle S1 1 3b 3a SECRETION 2 FUSION brevin tagmin ACTION MACHINE POTENTIAL (AP) Ca entry S-25 membrane exin membrane taxin OPENED BY ACTION POTENTIAL Ca channel Ca muscarinic GPCRs AChE ACh 5 4 4 hydrolysis SMOOTH OR CARDIAC MUSCLE

  44. SYMPATHETIC NERVE TERMINAL NE vesicle S1 1 L 3b NE 3a SECRETION 2 FUSION brevin tagmin ACTION MACHINE POTENTIAL (AP) Ca entry S-25 NET SLC6A2 membrane exin membrane taxin OPENED BY ACTION POTENTIAL Ca channel Ca NE NE From Dr. George’s Transport lecture

  45. SYMPATHETIC NERVE TERMINAL NE vesicle S1 1 L 3b NE 3a SECRETION 2 FUSION brevin tagmin ACTION MACHINE POTENTIAL (AP) Ca entry S-25 NET SLC6A2 membrane exin membrane taxin OPENED BY ACTION POTENTIAL Ca channel Ca NE GPCRs α1 or β1 NE 4 SMOOTH OR CARDIAC MUSCLE

  46. Pilfered from Dr. Cochard Sympathetic

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