1. Introduction to the Autonomic Nervous System George Howell III, Ph.D

2. Nervous system hierarchy Enteric Nervous System

3. Autonomic nervous system Independent – activities are not under direct conscious control (autonomic = automatic) Divided into parasympathetic, sympathetic, and sometimes ENS on an anatomical basis Parasympathetic vs sympathetic divisions – Origin – IML vs CNS nuclei – Ganglia – paravertebral and prevertebral vs ganglia at target organ – Primary neurotransmitters – Ach vs NE

4. Origination of the PNS What’s missing??

6. Synapses of the PNS

7. Synaptic transmission 1.Synthesis of neurotransmitter from precursors 2.Action potential spreading depolarization 3.Activation of VGCa+ channels 4.Ca+ dependent fusion of neurotransmitter containing vesicles with plasma membrane 5.Release of transmitters into cleft and binding to postsynaptic receptors 6.Termination of transmitter action via degradation or reuptake in presynaptic 7.Activation of postsynaptic cell

8. Major neurotransmitters of the ANS Acetylcholine (Ach) – Fibers using Ach are cholinergic fibers – Almost all fibers leaving CNS are cholinergic – Major transmitter of preganglionic fibers (sympathetic and parasympathetic) – Major transmitter of parasympathetic postganglionic synapse and Nm junction Some parasympathetic postganglionics use peptides and NO as modulators – Nicotinic and muscarinic receptors Norepinephrine (NE) – Fibers using NE are adrenergic fibers – Major transmitter at sympathetic postganglionic synapse Some sympathetic postganglionics use Ach – Adrenergic receptors Alpha and beta

9. Other neurotransmitters of the ANS Dopamine – Modulator in some ganglia and ENS – Sympathetic transmitter in renal blood vessels Serotonin – Excitatory in ENS GABA – Inhibitory Substance P – Sensory neurotransmitter – Excitatory with Ach at Nm junction, vasodilator due to NO release, nociception at peripheral nerve synapses Vasoactive intestinal peptide – Excitatory secretomotor transmitter in ENS, vasodilator, cardiac stimulant Adenosine triphosphate (ATP) – Transmitter or cotransmitter at ANS effector synapses Enkephalins and other endogenous opioids – Inhibitory effect on secretomotor interneurons in ENS, inhibit peristalsis, stimulate secretion Gastrin releasing peptide (GRP) – Promotes gastrin release from G cells in stomach Neuropeptide Y Nitric oxide (NO) – Synthesized on demand by NOS…..not stored – Vasodilation

10. Cholinergic synapse Synthesis of acetylcholine – Choline is taken up into presynaptic cell by Na+ dependent choline transporter (rate limiting step) – Acetyl CoA + choline = acetylcholine Catalyzed by choline acetyltransferase – Transported into vesicles by vesicle associated transporter (VAT) Other cotransmitters are also stored in vesicle Vesicular release – v-SNAREs (synaptobrevin; subgroup of VAMPs) bind with t-SNAREs (SNAPs; syntaxin and SNAP-25) to mediate vesicular fusion Ca+ dependent Blocked by botulinum toxin Presynaptic and postsynaptic responses to Ach (muscarinic and nicotinic receptors) – Presynaptic receptors – auto and heteroreceptors Acetylcholinesterase mediated degradation – Acetylcholine to choline + acetate – Terminates action of acetylcholine in cleft

11. Cholinergic receptor subtypes and actions Nicotinic Ligand gated Na+ channels Directly mediate depolarization in excitable cells Two subtypes: neuronal (Nn) and muscular (Nm) Muscarinic GPCRs 5 subtypes M1, 3, 5 are coupled to Gq G- proteins M2, 4 are coupled to Gi G-proteins

12. Role of each cholinoceptor at autonomic ganglia Nn – milliseconds – Excitatory postsynaptic potential (EPSP) – Temporal or spacial summation leads to AP M2 – seconds – Inhibitory postsynaptic potential (IPSP) – Follows AP – Mediated by opening of K+ channels M1 – seconds – Slow EPSP by closing K+ channels – Follows IPSP Peptides – minutes – Late, slow EPSP – Modulates response of postsynaptic cell to subsequent inputs

13. Adrenergic synapse Synthesis of NE Vesicular transport VMAT Dopamine converted to NE in vesicle Neurotransmitter release Vesicular fusion similar to that of the cholinergic synapse Neurotransmitter actions Postsynaptic and presynaptic receptors Transmitter reuptake NET and DAT terminate neurotransmitter action

14. Adrenergic receptor subtypes and actions Alpha GPCRs Two subtypes A1 – Gq protein coupled A2 – Gi protein coupled Beta GPCRs Three subtypes B1-3 – Gs protein coupled

15. Autonomic regulation of organ systems

16. Autonomic regulation of cardiovascular function Baroreceptor reflex Increase in MAP Increased baroreceptor firing Increase parasympath etic tone Decrease sympathatic tone Decrease in MAP Decreased baroreceptor firing Decrease parasympath etic tone Increase sympathetic tone

17. Enteric Nervous System Large and highly organized system of neurons located in the walls of the gastrointestinal system It is often considered a third division of the autonomic nervous system Includes the myenteric plexus (of Auerbach) and the submucous plexus (of Meissner)

18. Enteric nervous system Myenteric plexus Submucosal plexus Longitudinal muscle Circular muscle layer Parasympathetic Walls constricted and sphincters relaxed via M3 Secretions increased via M3

19. Autonomic regulation of structures associated with the eye Dominant tone = Parasympathetic Iris radial – contracted via alpha-1 Iris circular – contracted via M3 Ciliary muscle – contracted via M3

20. Regulation of the heart Dominant tone = parasympathetic Sympathetic Increases heart rate and contractility via beta-1 and 2 (primarily beta-1) Parasympathetic Decreases heart rate and atrial contractility via M2

21. Regulation of the blood vessels Veins Dominant tone = parasympathetic Arterioles/arteries Dominant tone = sympathetic Contraction via alpha1 Relaxation via beta-2

22. Regulation of the liver Sympathetic – Increase gluconeogenesis and glycogenolysis – Provide glucose to fuel “flight or fight” response – Primarily beta-2, possibly alpha-1

23. Control of stomach acid Parasympathetic Increase histamine release from ECL cell via M3 Increase H+ production from parietal cell in fundus via M3 Decrease somatostatin release from D cell in antrum Increases gastrin release from G cell

24. Regulation of the bladder Parasympathetic Bladder wall – Constriction via M3 – Relaxation via beta-2 Sphincter – Relaxation via M3 – Constriction via alpha-1

25. Glandular secretion Sweat Salivary Appocrine – increased via alpha-1 Eccrine – increased via M Increased via M3 Lacrimal gland (tear production) – increased via M

26. Predominant tones of major organ systems Heart - parasympathetic Arterioles/arteries - sympathetic Veins - sympathetic Iris - parasympathetic Ciliary muscle - parasympathetic GI tract (ENS) - parasympathetic Smooth muscle - parasympathetic Bladder - parasympathetic Sweat glands - sympathetic Salivary glands – parasympathetic Lacrimal glands – parasympathetic

27. Physiological effects of autonomic innervation and receptors that govern the effect Parasympathetic Sympathetic Contracts the ciliary muscle via M-3 Decelerates the sinoatrial node via M-2 Decreases heart contractility via M-2 Releases EDRF in the endothelium via M-3, M-5 Contracts bronchiolar smooth muscle via M-3 Contracts GI walls via M-3 Relaxes GI sphincters via M-3 Increases GI secretions via M-3 Contracts the uterus via M-3 Causes erection of the penis via M Contracts the iris radial muscle via alpha-1 Relaxes the ciliary muscle via beta Accelerates the sinoatrial node via beta-1,2 Accelerates ectopic pacemakers via beta-1,2 Increases cardiac contractility via beta-1,2 Relaxes bronchiolar smooth muscle via beta-2 Relaxes GI walls via alpha-2, beta-2 Contracts GI sphincters via alpha-1 Relaxes bladder wall via beta-2 Contracts bladder sphincter via alpha-1 Contracts uterus via alpha, relaxes uterus via beta-2 Contracts pilomotor smooth muscle via alpha Activates sweat glands via alpha, M Increases gluconeogenesis and glycogenolysis in liver via beta-2 and alpha Induces lipolysis via beta-2 Increases renin release from kidney via beta-1