Biology 48 - Human Physiology Lecture 14 Neurotransmitter Modes of Action

Neurotransmitter:

• Mechanism of action:

a. Specific for each : c Ligand: Substance that is able to bind and form:

ü Ligand = b. Two primary strategies utilized: c Receptor ligand complex cause: 1. 2. Specific Examples: 1. Acetylcholine (ACh): • Released from: a. ALL : b. Many : c. 3/4 : • ACh exerts Differential Effects on Target Cells a. Excitatory Neurotransmitter ➫ ó ➫ Skeletal Muscle: b. Inhibitory Neurotransmitter ➫ ó ➫ Cardiac Muscle: Question: “How can the same neurotransmitter cause different effects?” Answer:

ü It is NOT the neurotransmitter that determines the: ü It IS: the different : a. Nicotinic ACh Receptor: • Function: ó Nicotinic Receptor-ACh complex: ➫ Na+/K+ Channel:

• ó Na+ Influx: ó K+ Efflux: ➫ Overall effect:

b. Muscarinic ACh Receptor: • 5 Receptor Subtypes: w/in CNS and PNS M1 / 3 – Smooth muscle & Glands M2 – Cardiac Tissue M4 / 5 - CNS Simplistic view: • Function: G-protein moderated / Second messenger Operated Channel ➫ Receptor: ➫ Receptor is NOT : • Activate Membrane bound enzyme: ➫ Produces: cytoplasmic molecule: ➫ Second Messenger : • Membrane bound Enzyme ➫ Second Messenger 1. Adenylate Cyclase ➫ cAMP 2. Phospholipase ➫ IP3 ó G-Protein sub-units dissociate: ➫ Move through membrane: Bind membrane bound :

➫ PROTEINS stimulate: Opening and/or Closing of Ion channels

a. K+ Ion Channel : K+ efflux: Hyperpolarization (IPSP) b. Ca2+ or Na+ Ion Channel : Ca2+ & Na+ influx: Depolarization (EPSP) Ca2+ & Na+ influx:

ACh Receptors Examples 1. Skeletal Muscles: Nicotinic ACh Receptor

ó EPSP opens voltage gated ion channels

c Initiate muscle: 2. Cardiac Muscle: Muscarinic ACh Receptor (M2) ➫ G-proteins : Activate : * Adenylate cyclase: Produces * cAMP: Inhibits ➫ G-proteins Stimulate : * Result: Efflux of ➫ (IPSP) Hyperpolarization: ACh : 3. Smooth Muscle (GI Tract): Muscarinic ACh Receptors (M3) ó G-protein sub-units: Activate : ó PLC: Produces: ó IP3: Opens : ó Influx Ca2+ & (EPSP) : ➫ ACh INCREASES :

• Signal Termination: “How are the signals turned OFF?” ó Stimulation dependent upon presence of :

ó Channels remain open as long as : ✔ STOP stimulation: Neurotransmitter must be : Acetylcholine: Signal termination

� Acetylcholinesterase (AChase)

ó ACh : c Present w/in : ó AChase : c c ACh binds Receptor & AChase equally

✔Over time ACh concentrations : Clinical Applications: • Myasthenia Gravis = “Muscle weakness”

óAuto-immune Disease: ó Treatment: (Neostigmine) Monoamine Neurotransmitters • Family of Neurotransmitters

óDerived from :

➫ Tryptophan: Serotonin: ➫ Tyrosine: Norepinephrine, & Dopamine: ó Catecholamines Monoamine: Mode of Action • Receptor-Ligand Complex: G-Protein Moderated Second Messenger Operated

Steps in Monoamine pathway 1. G-proteins: Sub-units dissociate when : ó Subunits activate a :

ó Enzyme: 2. Adenylate Cyclase Enzyme

óConverts ATP into : c Cyclic AMP:

ü Molecule initiating secondary : 3. cAMP: Second Messenger

ó Activates a cytoplasmic : c Kinases: Common cellular : ü Phosphorylate: Add Phosphate to cellular proteins : c Produce : 4. Phosphorylated proteins:

ó Open c Results in: ó AND can produce : c Result: � Significance: Second Messengers Link

Monoamine (MA) Signal Termination: ➫ 2 Main Modes of Monoamine Removal:

1. Re-uptake:

Cocaine: Blocks Reuptake Increases: Addictive:

2. Enzymatic Degradation: 2 types

a. Monoamine Oxidase: MAO ➫ Oxidize Monamines: Cause

b. Catechol-O-Methyltransferase (COMT) ➫ Add methyl group to Catecholamine: Cause

Clinical Applications: 1. Clinical Depression: ó Serotonin (CNS) Moderate Mood, appetite, cognition, sleep, perception ➫ Low levels associated with : ó Depression Treatment:

a. MAO Inhibitors: Decrease Serotonin

➫

b. Monoamine Re-uptake Inhibitors ó Decrease Serotonin Re-uptake ➫ (SSRI’s : Serotonin specific Reuptake inhibitors)

Inhibitory Neurotransmitters: } GABA: gamma aminobutyric acid ◦ Most common neurotransmitter in :

◦ Mechanism:

◦ Opens Cl- channels causing:

Study Questions : 1.What are the two strategies utilized by receptor ligand complexes to stimulate target cells? 2. Explain how a single neurotransmitter (ie ACh) can function as both an excitatory and an inhibitory neurotransmitter. 3. Where would one find ACh being released ? 4. Describe the difference between Ligand Operated Ion Channels and G-protein Moderated Second Messenger Operated Ion Channels in how the ion channels are opening. 5. Explain why the binding of ACh to nicotinic receptors results in muscle contraction? Why do nicotinic receptors flux K+ at the same time as they flux Na+? 6. Muscarinic receptors function to indirectly open ion channels. In general what happens to the muscarinic receptor when bound to a neurotransmitter? 7. What is the difference between a stimulatory G protein and an inhibitory G protein on the postsynaptic cell membrane? What kind of ion channel changes might a stimulatory g protein cause? 8. Muscarinic receptors function to indirectly open ion channels. This can be done by neurotransmitter decreasing the affinity of the associated G-proteins. The G proteins will in turn either bind the associated ion channels (opening or closing them) or activate a membrane bound enzyme that produces a second messenger. Diagram these two strategies of channel opening by G-proteins . Use the M2 cardiac receptors as an example. 9. The Vagus nerve is a parasympathetic nerve and functions by releasing ACh onto target tissue. As you know, parasympathetic neurons function to coordinate the “Rest and digest” activities. What effect (stimulatory or inhibitory) would you expect occur when ACh binds muscarinic receptors on the : heart, digestive tissues, and blood vessels to the muscle (nicotinic or muscarinic)? 10. Can ACh have a continued affect on the target tissue, even if the pre-synaptic neuron has stopped releasing the neurotransmitter? Explain. 11. Nerve gas functions to elicit its odious effects by inhibiting Acetylcholinesterase. What symptoms would be presented in an individual poisoned with nerve gas? 12. Botulinus bacteria secrete a Botulinus toxin. The toxin functions by specifically inhibiting the release of peripheral tissue Nicotinic ACh by digesting the fusion complex. What clinical treatment might alleviate these symptoms? 13. Curare is a poison used by many South American Indians. It functions by competing for the attachment of ACh on nicotinic receptors. What effects would curare have on the skeletal muscle ? 14. What are monoamines? What are catecholamines ? 15. Describe how G-protein activation results in opening of ion channels. What is a second messenger? 16. What three strategies are used by cells to remove monoamines from the synaptic cleft? 17. Depression can result from decreased concentrations of serotonin. If you were designing a drug to alleviate depression, what are some of the various modes of action you might try to employ? 18. Explain how the second messenger method of activation promotes increased cellular responses. 19. Describe some of the clinical uses of MAO inhibitors. 20. Explain how GABA functions to cause an inhibitory affect on postsynaptic neurons.