Module 2D (Pt3) Flashcards
What are the junctional transmission steps
- Storage and release of the transmitter
- Post junctional potential
- Initiation of post junctional activity
- Destruction or dissipation of the transmitter
- Non electrogenic functions
Storage and release of the transmitter
the neurotransmitter is packed into synaptic vesicles in the axon
Post junctional potential
the transmitter crosses the synaptic cleft, interacts with a receptor and evokes a response from the post synaptic neuron
Initiation of post junctional activity
summation of responses caused by the transmitter(s) results in a change in the post synaptic neuron
Destruction or dissipation of the transmitter
enzymes, reuptake pumps, or simple diffusion limit the transmitters signal
Non electrogenic functions
continual quantal release is a homeostatic control for maintaining receptor, enzyme and pump levels
What are receptors
- Biological molecules (often proteins) that are selective in their ligand-binding characteristics and modifiable when a ligand is bound so as to produce a functional change
What is a receptor site for a drug (ligand)
- Is the specific binding region of the receptor
- Has a high and selective affinity for the drug molecule
What initiates the action of the drug
- The interaction of a drug and its receptor
Receptor
a molecule to which a drug binds to bring about a change in a biological system
Receptor site
specific region of the receptor molecule to which a drug binds to
Effector
component of the system that accomplishes the biological effect
Spare receptor
receptor that doesn’t bind agonist when drug concentration is sufficient to produce max effect Kd> EC50
Agonist:
a drug that activates its receptor
Antagonist
a drug that binds without activating its receptor and prevents activation by agonist
-(competitive, irreversible, physiologic, chemical, inverse)
What causes regulation in receptors
- Number, location, interaction with effectors
- Desensitization, tachyphylaxis (become down regulated if over used)
- Internalization
- Substrate depletion
- Down or up regulation
What are ionotropic receptors
- Ligand-gated ion channels
- Rapid response (microseconds)
- Often more then 1 subunit (oligomeric
- Examples are nAChR (Ach receptor, Na channel)
What are metabotropic receptors
- G protein coupled receptors
- Slower, modulatory response (milliseconds/ seconds)
- Single 7 helix subunit
- Example is mAChR (Ach receptor)
- BAR (norepinephrine receptor)
Cholinergic transmission steps
i) Acetylcholine synthesis
ii)Choline transport and storage
iii)Release of Ach by SNAREs: CAMPs and SNAPs
iv)Ach degradation
Acetylcholine synthesis
- Occurs through choline acetyltransferase (ChAT)
i) ChAT transfers an acetyl group from acetyl-CoA onto choline
ii) Acetyl- CoA synthesized by pyruvate dehydrogenase in mitochondria
iii) Choline is brought into the axon terminal by active transport
Choline transport and storage
- Occurs through the enzymes choline transporter (CHT1) and vesicular Ach transporter (VAChT)
i) CHT1 brings choline into the axon- ATP- dependent (active transport), rate limiting
- Inhibited by hemicholiunium (not used clinically rather for research)
ii) CAChT brings Ach into synaptic vesicles - Atp dependent
- Inhibited by vesamicol
- 1,000- 50,000 Ach/ vesicle
- About 300,000 vesicles in an axon
Release of Ach by SNAREs: VAMPs and SNAPs
i) When an axon terminal depolarizes
- Voltage gates Ca channels open
- Ca allows for interactinos between Vesicle-associated Membrane proteins (VAMPs) and synaptosome associated proteins (SNAPs) on the vesicles and membrane
- Membrane fusion occurs, allowing Ach (and co trasnmitters) to exit the cell by exocytosis
- Ach release is inhibited by botulinum toxin
ii) 2 ACh pools
- The readily releasable pool
- The reserve pool
Ach degradation
- Occurs through acetylcholinesterase (AChE)
i) Ach Is broken down quickly in the synaptic cleft- AChE hydrolyzes Ach into acetate and choline, both are recycled
- Ach is present in the synapse or neuromuscular junction for < 1 millisecond
- Inhibition of AChE is therapeutically important (and potentially toxic) effect of many drugs
If you were to give someone botulism toxin would you be promoting or inhibiting the sympathetic nervous system
- Net effect is blocking ach so your promoting sympathetic nervous system as you are inhibiting the parasympathetic
- Look at the end effector
How many homologous subunits are in nicotinic acetylcholine receptor
- 5 homologous subunit form Na+/K+ pore
- Subdivided based on location and their ability to bind a bungarotoxin
What are m nAChR
Muscle receptor
Where are Neuronal type nAChR:
- Exist in peripheral ganglia, adrenal medulla, and brain as homopentamers and heteropentamers (Nn)
What do peripheral Nn
Depolarization and firing of post ganglionic neurons, secretion of catecholamines
What are muscarinic acetylcholine receptors
- Get name from muscimol, from mushrooms (mimics and activates the effects of the parasympathetic nervous system)
- 5 distinct subtype (1-5)
- All GPCRs with different roles
What are the Gq coupled GPCRs
- M1,3,5
Important in smooth muscle fibers (in gut, eye…)
What are the Gi coupled GPCRs
- M2,4
- I stands for inhibitory
- Does three things all at the same time
- Found mainly on muscles of heart (heart slows down)
Cholinergic actions in the body (Skeletal muscle, Autonomic ganglia, autonomic effector cells, Prejunctional sites, extra neuronal sites)
- Skeletal muscle
- Ach released from motor nerve-> nAChR open-> skeletal muscle-> contraction
2. Autonomic ganglia - Ach released from pre-ganglionic nerve-> nAChR open -> EPSP in post ganglionic nerve
3. Autonomic effector cells - Ach released from post-ganglionic PNS nerve -> mAChR activated -> electrical activity is modulated
- Heart SA and AV nodes: increase K, hyperpolarization –> slowed heart rate
- Smooth muscle: Increase Na, Ca –> partial depolarization contraction via Ca
4. Prejunctional sites - Negative feedback via M2 and M4
5. Extra neuronal sites
- Ach released from motor nerve-> nAChR open-> skeletal muscle-> contraction
What are cholinomimetics also called
- Parasympathomimetic
What are cholinomimetics clinically useful
- Glaucoma
- Loss of normal function in bowel and bladder
- Smoking cessation
Muscarinic toxicity
- Miosis, bronchoconstriction, excessive GI activity, sweating, vasodilation, slowing of heart rate followed by reflex tachycardia (vagus nerve kicks in)
Explain nicotinic toxicity
- Fasciculations and paralysis, stimulation (convulsions) and then depression, addiction
What happens when AChE is inhibited
- DUMBBELSS
- Diarrhea, urination, miosis, bronchoconstriction, bradycardia, excitation (skeletal muscle and CNS), lacrimation, salivation, sweating
What are muscarinic antagonists clinically useful in
- Scopolamine: nausea
- Atropine: treating miosis, reducing airway secretion, reducing diarrhea and gastric secretions (in the past), treating AChE intoxication
- Ipratropium: bronchodilation in asthma
- Oxybutynin: bladder spasm
Toxicity in muscarinic antagonists
- Hyperthermia (through inhibition of sweating), dry mouth, tachycardia, arrhythmia, acute angle glaucoma, urinary retention, constipation, blurred vision, flushing (redness), sedation, delirium and hallucinations
What are nicotinic antagonists useful in (clinically)
- Hypertensions (hexamethonium)
Are nicotinic antagonists used clinically often
Rarely used clinically
Toxicity of nicotinic antagonists
- Venous pooling and postural hypotension
- Dry mouth, blurred vision
- Constipation
- Sexual dysfunction
look at extending concepts
