Peripheral Nervous System: Neurotransmitters and Receptors The Peripheral Nervous System Efferent nervous system Somatic nervous system (non-autonomic,voluntary) Skeletal muscle Autonomic nervous system Heart.blood vessels. (vegetative,visceral,involuntary glands,other visceral enteric nervous system) organs,smooth muscle Somatic and visceral afferent nerves Anatomic classification:sympathetic(fight or flight) parasympathetic(rest and digest) Neurotransmitter-based classification:adrenergic,cholinergic,dopaminergic 1
1 Neurotransmitters and Receptors Peripheral Nervous System: Efferent nervous system Somatic nervous system (non-autonomic, voluntary) Skeletal muscle Autonomic nervous system (vegetative, visceral, involuntary; enteric nervous system) Heart, blood vessels, glands, other visceral organs, smooth muscle The Peripheral Nervous System Somatic and visceral afferent nerves Anatomic classification: sympathetic (fight or flight) parasympathetic (rest and digest) Neurotransmitter-based classification: adrenergic, cholinergic, dopaminergic
Otto Loewi(Nobel Laureate,1936) He discovered that stimulation of the vagus of a frog heart causes release of a substance that.when transferred to a second heart,could slow heart rate.He called this"Vagusstoff",demonstrating the chemical basis of neurotransmission. He also found that atropine can prevent the inhibitory action,but not the release of the "Vagusstoff". Incubation of the"Vagusstoff"with frog heart homogenate inactivates it. Physostigmine enhances the effect of vagus stimulation on the heart,and prevents the destruction of"Vagusstoff. On mature consideration,in the cold light of the morning,I would not have done it.After all,it was an unlikely enough assumption that the vagus should secrete an inhibitory substance;it was still more unlikely that a chemical substance that was supposed to be effective at very close range between nerve terminal and muscle be secreted in such large amounts that it would spill over and,after being diluted by the perfusion fluid,still be able to inhibit another heart.(Loewi 1921) 2
2 • He discovered that stimulation of the vagus of a frog heart causes release of a substance that, when transferred to a second heart, could slow heart rate. He called this “Vagusstoff”, demonstrating the chemical basis of neurotransmission. Otto Loewi (Nobel Laureate, 1936) • He also found that atropine can prevent the inhibitory action, but not the release of the “Vagusstoff”. • Incubation of the “Vagusstoff” with frog heart homogenate inactivates it. • Physostigmine enhances the effect of vagus stimulation on the heart, and prevents the destruction of “Vagusstoff”. On mature consideration, in the cold light of the morning, I would not have done it. After all, it was an unlikely enough assumption that the vagus should secrete an inhibitory substance; it was still more unlikely that a chemical substance that was supposed to be effective at very close range between nerve terminal and muscle be secreted in such large amounts that it would spill over and, after being diluted by the perfusion fluid, still be able to inhibit another heart. (Loewi 1921)
Neurotransmitter: A chemical that transmits signals from one neuron to another or from a neuron to an effector cell. Chemical (intracellular messengers) Electrical Stimulation ·Chemical Physiological (impulse） (neurotransmitter） functions Electrical (membrane ion channels) Definition of synapse: A junctional connection between two neurons,across which a signal can pass Pre-synaptic neuron:Where a neurotransmitter is synthesized,stored and released upon cell activation. Post-synaptic neuron or effector cell:Where neurotransmitter is detected and its action translated into cellular activities. 3
3 Electrical Stimulation (impulse) Chemical (neurotransmitter) Neurotransmitter: A chemical that transmits signals from one neuron to another or from a neuron to an effector cell. Chemical (intracellular messengers) Electrical (membrane ion channels) Physiological functions Pre-synaptic nerve cell Post-synaptic nerve cell Synaptic cleft Ca2+ Na+ Precursors (choline/tyrosine) Definition of synapse: A junctional connection between two neurons, across which a signal can pass Precursor Neurotransmitter Storage Release Recognition by receptors Metabolic disposition Pre-synaptic neuron: Where a neurotransmitter is synthesized, stored and released upon cell activation. Post-synaptic neuron or effector cell: Where neurotransmitter is detected and its action translated into cellular activities
CNS Pre-ganglionic Ganglion Post-ganglionic Effectors lelueJo Parasympathetic Ach Cardiac smooth muscles,gland cells Nicotinic Muscarinic nerve terminals Sympathetic NE Cardiac smooth muscles,gland cells, Adrenergic nerve terminals Ach (c.B) Sympathetic Ach Sweat glands Nicotinic Muscarinic Sympathetic D Renal vascular smooth muscle D1) nergic Sympathetic(adrenal medulla) Ach Epi Released into blood Nicotinic leJoes Motor(somatic) Skeletal muscle Nicotinic Ach=acetylcholine D=dopamine Epi=epinephrine NE norepinephrino Pharmacological division of cholinergic vs.adrenergic neurotransmission All preganglionic and parasympathetic postganglionic neurons use acetylcholine as neurotransmitter.Ach is the neurotransmitter at ganglia, nmj,and muscarinic tissue synapses. Most postganglionic sympathetic neurons use norepinephrine which is an adrenergic neurotransmitter. There are exceptions:Cholinergic transmission in sympathetic system- all ganglia,adrenal medulla,sweat glads(muscarinic).Dopaminergic innervation in sympathetic system-renal blood vessels. 4
4 Thoracolumbar Cranial Sacral CNS Pre-ganglionic Ganglion Post-ganglionic Parasympathetic Ach Nicotinic Ach Nicotinic Ach Nicotinic Ach Nicotinic Ach Nicotinic Epi Sympathetic Sympathetic Sympathetic Sympathetic (adrenal medulla) Motor (somatic) Ach Ach Muscarinic Muscarinic NE Adrenergic (α, β) D Dopaminergic (D1) Ach Nicotinic Cardiac & smooth muscles, gland cells, nerve terminals Cardiac & smooth muscles, gland cells, nerve terminals Sweat glands Renal vascular smooth muscle Released into blood Skeletal muscle Ach = acetylcholine D = dopamine Epi = epinephrine NE = norepinephrine Effectors • All preganglionic and parasympathetic postganglionic neurons use acetylcholine as neurotransmitter. Ach is the neurotransmitter at ganglia, nmj, and muscarinic tissue synapses. • Most postganglionic sympathetic neurons use norepinephrine which is an adrenergic neurotransmitter. Pharmacological division of cholinergic vs. adrenergic neurotransmission • There are exceptions: Cholinergic transmission in sympathetic system – all ganglia, adrenal medulla, sweat glads (muscarinic). Dopaminergic innervation in sympathetic system – renal blood vessels
Key Steps in Neurotransmission: Synthesis Storage Metabolism Action potential Recognition (action) Strategies for Pharmacological Intervention: Block synthesis and storage: Usually rate-limiting steps;produce long-term effects Block release: Rapid action and effective Interfere with metabolism: Can be reversible or irreversible:blocking metabolism increases effective neurotransmitter concentrations Interfere with action: Receptor antagonists agonists;high specificity Synthesis of acetylcholine: Choline Acetylcholine CH、 CH3 0 CH3-N'-CHz-CHz-OH Choline CH3-N+-CHz-CHz-O-C-CH3 CH3 acetyltransferase CH3+ 0 CoA-SH CoA-S-C-CH3 Acetyl-CoA CoA 5
5 Synthesis & Storage Action potential Metabolism Recognition (action) Key Steps in Neurotransmission: Strategies for Pharmacological Intervention: Block synthesis and storage: Usually rate-limiting steps; produce long-term effects Block release: Rapid action and effective Interfere with metabolism: Can be reversible or irreversible; blocking metabolism increases effective neurotransmitter concentrations Interfere with action: Receptor antagonists & agonists; high specificity Release Synthesis of acetylcholine: CH3 CH3 CH3 N+–CH2–CH2–OH CoA–S–C–CH3 O Choline Acetyl-CoA + Choline acetyltransferase CH3 CH3 CH3 N+–CH2–CH2–O–C–CH3 O CoA-SH + CoA Acetylcholine