ACh and others

which groups of neurons do cholinergic pathways arise from?

1. Pedunculopontine (PPT)/ laterodorsaltegmentum (LD)​

2. Magnocellular forebrain (Nucleusbasalis and septohippocampal)) ​

3. Striatal interneurons​

Name 4 differences between nicotinic (nAChR) and muscarinic (mAChR) acetylcholine receptors (2 marks).

differences

• muscarinic can be either excitatory or inhibitory whereas nicotinic is excitatory only

• nicotinic receptors are pentamers whereas muscarinic receptors are mainly monomers

• nicotinic receptors are ligand gated ion channels whereas muscarinic receptor are GPCR

• nicotinic receptors can bind 2 or more acetylcholine where muscarinic binds one only

• nicotinic receptors have faster transmission than muscarinic

pednuculopontine and laterodorsaltegmentum nuclei

• found in brainstem

• send projections to thalamus

• play important role in arousal and sleep wake regulation

Magnocellular neurons of the basal forebrain

project widely to the cerebral cortex, providing cholinergic input that supports attention, learning, and memory.​

Septal nuclei

• basal forebrain

• send cholinergic projections to the hippocampus, contributing to memory formation and spatial navigation.​

draw the distribution of the cholinergic neurons

roles of acetylcholine

• Arousal, learning and memory​

• Pontine nuclei – arousal, sleep/wake​

• Magnocellular forebrain – arousal​

• Septohippocampal – learning (short term)​

• (striatal interneurons – motor control)​

why are knockouts not useful for roles of ACh

• the receptor subtypes can overlap so it is hard to isolate function/effect

• inducible knockouts may provide more information

acetylcholine receptors structure and key information table

draw the cholinergic terminal

NMJ transmission of ACh (5 marks)

• vesicle full of ACh fuses with the membrane and releases

• ACh binds to nicotinic acetylcholine receptor on postsynaptic membrane (2 molecules each)

• acetylcholine is broken down in the synapse by AChE into acetate and choline

• choline is taken up by presynaptic terminal, joins with acetyl coa and forms acetylcholine

FAST SYNAPTIC TRANSMISSION

neuronal nicotinic transmission

• dopamine is released from vesicles into synapse with calcium dependent manner

• calcium voltage gated channels

• nicotinic acetylcholine receptors which allow further calcium entry and enhance dopamine release - heteroreceptor

muscarinic cholinergic transmission

• similar to periphery

• acetylcholine binds to M2, M4, coupled to adenylate cyclase via Gi, inhibitory, often found on presynaptic nerve terminal

• M1, M3 and M5 found on postsynaptic and foreign spaces, excitatory Gq coupled, inc calcium signalling

nicotinic receptor structure adult skeletal muscle

• 2 x alpha 1 subunits

• beta 1

• delta

• epsilon

• permeable to sodium, potassium and calcium

autonomic ganglia nicotinic receptor structure

• alpha 3 ×2

• beta 4 × 3

brain nicotine binding site

• alpha 4 ×2

• beta 2 ×3

brain bungarotoxin binding site

• 5 x alpha 7

nAChR gating

• TM2 domains

• in resting state leucine bends inwards, quite large, hydrophobic

• activated state - rotation leads to leucine pointing away, serine pointing inwards, small, hydrophilic

where are M1 receptors located

• glands

• cerebral cortex

• autonomic ganglia

M1 receptor agonist therapeutic targets

• schizophrenia

• alzheimers

M2 receptor locations

• heart

• cns

• smooth muscle

M2 role and therapeutic antagonists

• modulate heart rate

• modulate smooth muscle

• → bradycardia, alzheimers, depression

M3 location

• glands

• smooth muscle - eye, bronchial tract, blood vessels

M3 role and therapeutic antagonists

• smooth muscle contraction

• exocrine secretion - saliva and tears

• → overactive bladder, asthma, IBS

M4 location

• CNS

• salivary glands

M currents

• arises from PIP2 gated potassium channels

• hyperpolarises, stabilises the RMP

which receptors activated shuts off M current

• M1, M3 and M5 - Gq coupled

• leads to depletion of PIP2

• cells become more excitable

darifenacin

• 30 fold M3 selective

• overactive bladder

where is histamine found

• mast cells in the brain

• magnocellular neurons in the posterior hypothalamus

histamine metabolism

• histidine → histamine with histidine decarboxylase

• N-methyltransferase

• Monoamine oxidase

• results in inactive metabolites

draw histaminergic synapse

H1 antagonists

• used widely therapeutically for allergies

• some cross bbb to produce marked sedation

• eg chlorophenamine and tripolidine

H2 receptors therapeutics

• used for ulcer treatment

• not much BBB penetration

neuropeptides

• Must be synthesised in soma

• produced as “pro” transmitter to be “finished” at the terminal​

• Stored in vesicles, Ca2+ dependent release ​

• Postsynaptic action on GPCR

theory for neuropeptides

• peptides eg VIP co exist with ACh in parasympathetic innervation of salivary glands

• low firing rates - only ACh

• high firing rates - both ACh and VIP

  • extension of dynamic range perhaps

examples of peptides

• Cholecyctokinin (CCK8)​

• Corticotrophin releasing factor (CRF)​

• Galanin​

• Neurotensin​

• Enkephalins, endorphins, dynorphins(opioid peptides)​

• Substance P​

• Calcitonin gene-related peptide​

• Vasopressin​

• Oxytocin​

• Neuropeptide Y​

• Vasoactive intestinal polypeptide (VIP)​

purines - adenosine

• adenosine can act as a neurotransmitter

• not vesicular - ATP dependent release

• acts on GPCR A1, A2A, A2B and A3

• form heteromers

• protective

• stabilisation

what do adenosine receptors form heteromers with?

• family A and C GPCR

• dopamine receptors

• mGluR

caffeine

• adenosine receptor antagonist

• A2A highest affinity

melatonin

• derived from tryptophan

• made in the pineal gland from 5HT

• driven by circadian light from retinal input

• 2 receptors MT1 and MT2 found in brain and retina

• anti jet lag drugs

NO

• produced by NOS, controlled by [Ca2+]i

• inhibitory and excitatory

• not synaptic or vesicular

• sometimes found as co transmitter

• role in LTP and LTD and neurotoxicity

lipids derived from arachidonic acid

• prostaglandins

• leukotrienes

• endocannabinoids

where are cabbinoid receptors expressed

• CB1 and CB2 throughout CNS and PNS

endocannabinoids - give 2 examples, mode of synthesis and termination

• Two main ECs: anandamide, 2-arachidonoyl glycerol (2-AG)​

• Synthesised as needed from membrane lipids​

• Termination: Endocannabinoid Membrane Transporter (EMT)​

endocannabinoid signalling retrograde vs paracrine

• retrograde is synthesised postsynaptically

• paracrine is synthesised from another terminal

• retrograde acts on presynapse whereas paracrine acts on different synapse with different transmitter

• paracrine releases GABA, autocrine releases glutamate

draw a diagram of both retrograde and paracrine endocannabinoid signalling