BRUNO MARS Flashcards by Tyler Baverstock

(1) Organisation of peripheral nervous system

Somatic NS (skeletal muscle)
Enteric NS (Gut)

AUTONOMIC NERVOUS SYSTEM (all targets except skeletal muscle)

Sympathetic NS (fight or flight)
Parasympathetic NS (Rest & Digest)

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(1) Different fibres within PNS

Afferent fibres: Carry sensory info to CNS

Efferent fibres: Carry signals from CNS to periphery

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(1) Synaptic transmission

1) Synthesis
2) Storage
- Protect
- Package (concentrated)
3) Release
- Docking of vesicle
- Ca2+ entry
- Fusion (exocytosis)
- Recycling (endocytosis)
4) Activation
5) Inactivation

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(1) Efferent pathways in ANS

1) Preganglionic neurones (arise in brain stem or lateral horn of spinal cord)
2) Postganglionic neurone (Nerve endings of Postgang neurones synapse with effector cells including smooth muscle, cardiac muscle, vascular muscule and exocrine glands)

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(1) Ach is the neurotransmitter released from…..

All the parasympetic postganglionic neurones at neuroeffector junction

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(1) NA is the neurotransmitter released from….

MOST postganglionic neurones of Sympathetic NS (except those innervating sweat glands: Ach)

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(1) Cholinergic synapses

Cholinoreceptors bind Ach

2 types:

1) Nicotinic: Activated by ACh and nicotine
2) Muscarinic: Activated by ACh and muscarine

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(1) Noradrenergic synapses

Adrenoreceptors bind NA

2 types:
Alpha
Beta

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(1) Types of receptors using NA and Ach

nACHR: Ligand-gated ion channels (pentamer)

mACHR, all adrenocetptors are GPCRs.

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(1) Organs innervated by PNS

Contriction of pupils
Constricts bronchi
Slow heart
Increases gut motility and secretion
Contracts bladder
Erects genitals

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(1) Organs innervated by SNS

Dilates pupils
Contricts blood vessels
Dilates bronchi
Increases HR and contractibility
Slows gut motility
Stimulates adrenaline production
Stims renal renin secretion
Stims liver to export glucose and FFA

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(2) Synthesis (in NMJ)

1) Choline acetyltransferase (ChAT) synthesises Ach from choline and Acetyl Coenzyme A (from Mito)

Reuptake of choline can be compet blocked by hemicholinium 3

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(2) Storage (in NMJ)

2) uptake and storage of Ach in synaptic vesicles is inhibited by vesamicol

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(2) Release (in NMJ)

3) Tetrodoxin (TTX) blocks voltage-gates Na+ channels (no action potential)

Voltage-gated Ca2+ channels blocked by conatoxins

Botulinum toxin blocks vesicle fusion

Dendrotoxins block voltage-gated K+ channes (more Ca2+ influx, more release)

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(2) Activation (in NMJ)

4) Release of vesicle gives a quanta of transmitter

At NMJ, each quanta gives a miniature end plate potential (mEPP) using acti of nAChRs

mEPPs summate to give end plate potential (EPP) which if large enough can cause action potential and cause muscular contraction

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(2) Inactivation (in NMJ)

5) Activation of nAChR at NMJ is terminated by AChE that breaks down Ach to acetate and choline

Drugs that inhibit AchE (anticholinesterases like nerve gases, neostigmine) increase conc and effects of Ach leading to muscle spasms

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(2) Competitive non-depolarising blocks (antagonists)

1) Tubocurarine
2) Vecuronium / Rocuronium

REVERSED BY ANTICHOLINESTERASES (e.g. neostigmine)

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(2) Depolarising blocker (agonist)

Suxamethonium

Used clinically for rapid onset of paralysis
short duration (broken down by plasmacholinesterases)

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(2) Effect of depolarrising blockers

PHASE 1 BLOCK

1) Persistent activation of endplate nAChR by suxamethonium
2) Prolonged depolarisation of endplate
3) Inactivation of voltage-gated Na+ channels

PHASE 2 BLOCK

4) Desense of endplate of nAChR
5) Repolarisation of endplate
6) Receptor desense maintains blockade

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(2) Effect of ganglion blockers

Reduced actions of both SNS and PNS

(2) Ganglionic Non-depolarising blockers (antagonists)

k-bungarotoxin
trimethaphan (compet)
Hexamthonium (non-compet open channel blocker)
Tubocurarine (non-compet)

(2) Ganglionic depolarising blockers (agonists)

Nicotine and lobeline
(nACh agonists)
-Repeatedly stim receptors to inactivate VG Na+ channels and desense nAChR

(3) Synthesis of Adrenaline

1) L-Tyrosine 
TYROSINE HYDROXYLASE
2) DOPA 
DOPA CARBOXYLASE
3) Dopamine
DOPAMINE-B-HYDROXYLASE
4) NA
PHENYLETHANOLAMIN N-METHYL TRANSFERASE

(3) Adrenoceptor diveristy

A-adrenoceptors (1,2)
NA > A&raquo_space; Isoprenaline

B-adrenoceptors (1,2,3)
Isoprenaline > A > NA

(3) Adrenorepctor actions

A1: contraction (vascular smooth muscle) A2: Decrease NA release (adrenergic nerve terminals) B1: Increase HR and force of contractions (cardiac muscle) B2: Dilation/relaxation (Cardiac/skeletal muscle blood vessels, bronchial smooth muscle) B3: Lipolysis (adipose tissue)

(3) Adrenreceptor messengers

A1: Gaq = PIP2 --> PKC, Ca2+ A2: Gai = cAMP --> decrease VGCC B1/2/3: Gas = cAMP, PKA

(3) Drugs on presynaptic terminal (storage)

Reserpine: Inhibits NA uptake, depletes NA. -Decrease in sympathetic function a-methyl DOPA: Converted to a-methyl NA, replaces NA, less potent than NA at A1, activates A2 less NA released. Decreases HR and BP

(3) Drugs on presynaptic terminal (release)

Bretylium: Taken up and stored in vesicles. Local aneasthetic action to block nerve conduction of noradrenergic neurones (long depletion of NA) Clonidine: A2 agonist, less NA released

(3) Alpha adrenoR antagonists

Prazosin: A1, decrease BP Labetalol: A/B, decrease BP via A1

(3) Beta adrenoR antagonists

Propranolol: B, decrease BP/HR Atenolol: B1, decrease HR, BP and cardiac Pindolol: partial agonist

(3) Use of salbutamol

B2: smooth muscle relaxation in asthma

(3) Tyramine

Stimulates NA release: 1) Competes with NA for U1 2) Displaces NA from vesicle

(3) Amphetamine

Stimulates NA release 1) Competes with NA for U1 2) Displaces NA from vesicle 3) Inhibits MAO

(4) Purinergic signalling

Inter-cellular signalling involving purine-based molcules

(4) ATP as a transmitter

Targets postganglionic sympathetic neurones (e..g. blood vessels) - Cause fast depolarisation/contraction of smooth muscle cells - Uses the P2X receptor

(4) Different purinergic receptors

P2X: Binds ATP P2Y: Binds ATP/ADP/UTP P0: Adenine P1: Adenosine

(4) Different ligand gated ion channels

Trimeric: ATP P2X Tetrameric: Glutamate Rs, AMPA/NMDA Pentameric: Nicotinic receptors, nAcHRs, GABAa

(4) Where is ATP and ADP

They are key in platelet aggregation

(4) Adenosine P1 receptors

They are all GPCRs A1: Gai/o = Reduction of PNS, SNS A2A: Gas = Inhibition of platlet aggragation, wound healing A2B: Gas, Gaq = Relaxation of smooth muscle in intestine A3: Gai = Enhancement of mediator release from mast cells

(4) Adenosine receptor antagonists

Theophylline/aminophylline

(4) Evidence in COPD on adenosine role

1) Elevated levels of Adrenosine in plasma and exhalaed breath condensate of patients with asthma and COPD 2) Aerosol adenosine exposure indcues bronchocontriction in patients with COPD but not in control 3) Non selective adenosine receptor antagonists improve lung funcion and symptions in asthma and COPD 4) Activation of adenosine receptors subtypes involved in COPD shown to elicit pro-inflam responses

(4) Why hard to create agonists and antagonists for ATP P2 receptors

Similarity between ATP P2 receptors make it difficult.

(5) 2 types of L-glutamate receptors

Ligand-gated ion channels: Ionotropic GluRs (Fast excitatory) (GLuR) GPCRs: Metabotropic GluRs (mGLuR) (slow modulatory)

(5) NMDA receptor

Tetramer: Glutamate binding site (GluN2), GLycine binding site (GluN1) -Transmembrane pore blocked by Mg2+

(5) Roles of glutamate receptors in mammalian brain

1) Mediate majority of fast exicitaory synaptic transmission in CNS 2) Implicated in host of neurodevelopmental, neurological and neurodegrerative conditons 3) Target of drugs of abuse like ketamine

(5) Active synapse

Transmits information at hyperpolarised (resting) membrane potentials through AMPA receptors

(5) Silent synapse

One that lacks AMPARs at synpase and does NOT transmit info at hyperpolarised (resting) membrane potentials due to Mg2+ block of the NMDA receptor. -AMPA receptors stored in intracellular vesicles at extrasynaptic sites

(5) Summary

Strength of synaptic transmission can be rapidly and bidirectionally regualted by AMPAR trafficking -Trafficking may underlie learning and memory, also patholgical and psychiatric conditons