BIOL 2048 - Autonomic Nervous system

roles of the ANS

• homeostasis —> sensory input leads to either hormonal or neuronal response

• pupilaary dilation

• dilation and constriction of blood vessels

• force and rate of heart beat

• secretion of glands

• energy metabolism - liver and skeletal muscle

anatomy of the ANS

GANGLION

• the first point of contact between the CNS and target tissue

• a group of nerve cell bodies

• outside the CNS

• the preganglionic neurons is in the CNS, the postganglionic is in the target tissue

sympathetic NS

• innervation from the spinal chord and the medulla

• organs are innervated at different levels of the CNS

• diffuse innervation —> few axons innervate an organ which is enough to maintain function but not enough for fine motor movements

EXCEPTIONS TO THE GENERAL RULES

• the kidneys post ganglionic neuron to the smooth muscle of the vascular bed releases dopamine instead of Ach

• for the adrenal gland: theres no synapse in the paravertebral sympathetic ganglion

• the synapse for teh adrenal gland is directly on the gland which releases Ach and activates nicotinic receptors

parasympathetic NS

• ganglia close to target organ

• widespread distribution of post ganglionic neuron in medulla or sacral segment of spinal chord

• discrete innervation of target tissues

co-ordination of the ANS

• regiond of the brain co-ordinate actions of the ANS

• amygdala: main limbic region for emotion

• hypothalamus: main integration centre

• reticular formation: most direct influence over autonomic function

general rules of the ANS

1. Ach regulated synapse at all ganglia in the ANS

2. in the sympathetic NS transmission at the postganglionic synapse usually involves noradrenaline acting on alpha/ beta adrenoreceptors

3. in the parasympathetic NS transmission at the postganglionic synapse usually involves Ach acting on muscarinic receptors

enteric nervous system

• innervated by both parasympathetic and sympathetic NS

• PS and S NS dont directly innervate the tissue —> they innervate the submucosal and myenteric plexus which innervates tissue

• chemoreceptors in gut send signals through the plexus to the CNS

dysautonomia - disregulation of the ANS

• damage to autonomic nerves

• fainting standing up, dizziness, sweating, inability to alter HR when excersising, digestive problems, urinary problems, vision problems

post ganglionic sympathetic synapse

• noradrenaline is the main transmitter at the post ganglionic sympathetic synapse

EXCEPTIONS

• sweat glands —> uses Ach

• resistance blood vessels in skeletal muscle which when activated drives vasodilation, done by adrenaline

structure of noradrenaline

• positive charge at physiological pH

• catechol group

• modification of the alpha and beta carbon will distinguish the family members from one another

synthesis of noradrenaline

false transmitters and interfering drugs

FALSE TRANSMITTERS

• enzymes must carry out reactions in the correct order otherwise false transmitters formed

• tyramine, octopamine, synephrine

INTERFERING DRUGS

• alpha methyl tyrosine is a competitive inhibitor for tyrosine hydroxylase —> used to treat phaeochromocytoma

• alpha methyl dopa can interfere with NArd transmission

parkinsons disease

• depletion of dopamine —> loss of motor function of neurons that dopamine controls

• can treat by giving the substrate for dopamine - levodopa as well as carbidopa which inhibits dopa decarboxylase

• carbidopa cant cross the blood brain barrier so L dopa—> dopamine only in the brain

• prevents dopamine outside the brain which is toxic

release of NAdr

• energy dependent

• stored in vesicles w ATP and chromogranin

• drugs that interfere w release of NAdr:

  • Reserpine: increases effect of sympathetic NS by causing vasoconstriction

  • antihypertensive w a side effect of depression

  • Guanethidine: antihypertensive w a saide effect of orthostatic hypertension

  • inability to control fast chages in bp

uptake mechanisms of NAdr

UPTAKE 1

• via noradrenaline transporter

• high affinity, low capacity

• located in the nerve terminal

• Na/K ATPase

• requires Na gradient and ATP

• drugs that block uptake 1 are antidepressants such as cocaine and impramine

UPTAKE 2

• low affinity, high capacity

• clears lots of NAdr but not quickly

• once uptake 1 has been exhausted, uptake 2 takes over

• extraneuronal

• cotransport of NAdr with sodium

• inhibited by cortisol

• not substrate dependent - can be used for other nts

release and metabolism of NAdr

RELEASE

• indirect sympathomimetics

• indirect because they don’t increase the sympathetic NS on their own nut increase adrenaline which mimics the effect of the SNS

• drugs that stimulate the release: tyramine from food, ephedrine in cold medicines and amphetamine in psychostimulants

METABOLISM

• two enzymes: MAO, catechol O methyl transferases (COMT)

• metabolites: 3 methoxy 4 hydroxymandelic acid and 3 methoxy 4 hydroxyphenylglycol —> used to measure ANS function

• can interfere w this pathway w MAO inhibitors (iproniazid)

adrenoreceptors

SUBTYPES OF RECEPTORS

• all GPCRs

• alpha subtype has isoforms 1 and 2

• beta subtype has 3 isoforms 1,2,3

ALPHA SUBTYPE

• a1 subtype found on synaptic neuron and is coupled to a Gq receptor which when bound will cause contraction of smooth muscle

• increases IP3 and DAG

• a2 subtype found in the presynaptic neuron and controls a feedback loop —> when NAdr binds to autoreceptor it inhibits the release of NAdr

• Gai decreases activity of calcium channels

BETA SUBTYPE

• all stimulate cAMP formation (Gas)

• all subtypes located in differnt place

• b1: controls

  • cardiac acceleration

  • lipolysis

  • gut motility

  • renin release

• b2 located in the bronchi and controls:

  • bronchodilation

  • vasodilation of blood vessels to skeletal muscles

  • glycogen breakdown

b adrenoreceptor antagonists

• propranolol: non selective b blocker

• antihypertensive

• atenolol is a selective b1 antagonist —> cardioselective

• slows down cardiac output

Ach synthesis and inhibition

• Ach regulates the ANS function at ganglia and the parasympathetic postganglionic synapse

• Substrates are acetyl CoA and choline

• rate limiting step is the uptake of choline by a choline transporter at teh presynaptic terminal

• choline acteyltransferase combines acetyl coa and choline and choline produced as a subproduct

• vesamicol can inhibit the choline transporter

Inactivation of Ach

• Ach degraded in the synaptic cleft by acetylcholinesterase —> choline and acetic acid

• Achesterase has an anionic site which attracts a +ve charge from N and estertic site which binds the carboxyl oxygen

receptors for Ach

• Dales experiment proved that there was more than one type of receptor for Ach

• nicotinic recptors at ganglia, muscarinic receptors at post ganglionic synapse

• some natural products can have a sympathomimetic or parasympathomimetic effect

  • muscarine, tobacco, atropine

MUSCARINIC RECEPTOR

• GPCRs

• specific to PSNS found in the postganglionic fibre

• muscarine acts as an agonist, no effect on the nicotinic receptors

• activates the PSNS

  • decreases HR

  • vasodilation

  • increased digestive tract

  • sweating and salivation

• receptor subtypes

  • M1 in the CNS —> located in the enteric NS and so can indirectly control gut motility

  • M2 in the heart

  • M3 located in diff glands

• antaginsts of the M receptors include atropine and pirenzipine

NICOTINIC RECEPTOR

• ligand gated sodium ion channel

• there are 5 subunits total and 2 subunits which allow 2 ach molecules to be bound (a subunits)

• receptor subtypes: Nn1/Nn2 (operate at the ganglia) or Nm type (NMJ)

• Ach and nicotine are agonists

• antagonists: polybismethonium family, classically hexamethonium

  • inhibits both the SNS and PNS by blocking the nicotinic receptor

  • members of the family with low no of carbons are particularly selective for the Nm type receptor whilst high no of carbons select for the Nn type —> distinguishes between inhibition of whole NS or just the NMJ