Exam #3: Review Material Flashcards
State whether the intracellular or the extracellular concentration is higher for the following ions: K+, Na+, Cl-, & Ca++. Will the chemical driving force of their concentration gradients tend to push these ions into the cell or out of the cell?
K+ = intracellular; pushed outside Na+ = extracellular; pushed inside Cl- = extracellular; pushed inside Ca2+ = extracellular; pushed inside
Describe the conductance changes during the action potential in terms of one gate for K+ and activation and inactivation gates for Na+. Be able to describe three possible states for the rapidly inactivating Na+ channel: resting (closed), activated (open) and inactivated.
Resting – K+ gate is closed, Na+ activation gates closed, Na+ inactivation gates open
Depolarization – K+ gate is closed, Na+ activation gate is open, Na+ inactivation gate is closed
Repolarization – K+ gate is open, Na+ activation gate is closed, Na+ inactivation gate is open
Hyperpolarization – K+ gate is open, Na+ activation gate is closed, Na+ inactivation gate is closed
Describe the threshold for action potential generation.
The threshold is the point at which the resting potential has become positive enough, due to depolarization, to fire the action potential, and is all or nothing
Describe briefly how the following diseases or toxin affects synaptic transmission: Myasthenia gravis. Is the problem pre-synaptic or post-synaptic? Is it an autoimmune diseases?
Myasthenia gravis – autoimmune; destroys postsynaptic nicotinic Ach receptors
Describe briefly how the following diseases or toxin affects synaptic transmission: Eaton-Lambert Syndrome. Is the problem pre-synaptic or post-synaptic? Is it an autoimmune diseases?
Eaton-Lambert Syndrome – autoimmune; damages presynaptic voltage-gated Ca2+ channels
Describe briefly how the following diseases or toxin affects synaptic transmission: Botulinum toxin. Is the problem pre-synaptic or post-synaptic? Is it an autoimmune diseases?
Botulinum toxin – cleaves SNARE proteins in the presynaptic motor neuron
Describe briefly how the following diseases or toxin affects synaptic transmission: α-bungarotoxin . Is the problem pre-synaptic or post-synaptic? Is it an autoimmune diseases?
α-bungarotoxin – IRREVERSIBLY blocks postsynaptic nicotinic Ach receptors
Compare and contrast the contractile components (structural components) utilized in smooth muscle and skeletal muscle.
- Smooth & skeletal muscle contain the same components (actin, myosin, & tropomyosin) , except smooth muscle DOES NOT contain TROPONIN
- Myosin heads in smooth muscle face in various directions, allowing for multi-directional contraction
- Dense bodies (smooth) = z-discs (skeletal)
- Smooth muscle cells can shrink and bulge
Review the contractile events that occur in skeletal muscle, starting with the attached state.
1) Myosin attached to actin
2) Myosin binds ATP leading to detachment
3) ATP hydrolysis to ADP & Pi resets the myosin head
4) Cross-bridge forms & myosin binds a new position on actin
5) Pi is released leading to a change in position of myosin–>power stroke
6) ADP released
How does the point of regulation differ from skeletal muscle to smooth muscle?
- Smooth muscle targets myosin
- Skeletal muscle uses Ca++ to regulate actin
Outline the events of contraction in smooth muscle.
1) Increased intracellular Ca++ from extracellular space
2) Ca++ binds Calmodulin
3) Calmodulin-Ca++ binds & activates myoskin light chain kinase (MLCK)
4) MLCK phosphorylates myosin regulatory chain & allows for activation of the myosin ATPase
5) Cross bridging occurs when myosin is phosphorylated at the regulatory chain
What is different between contraction of skeletal muscle & smooth muscle?
1) In smooth muscle ECF Ca++ is the PRIMARY source of Ca++, NOT SR Ca++ as in skeletal muscle
2) MLCK
3) Myosin ATPase is constitutively active in skeletal muscle; smooth muscle, this is regulated
4) Cross bridging occurs as long as myosin is in the phosphorylated state
Describe the events of actin-myosin cross-bridging in smooth muscle.
1) MLCK phosphorylates Myosin ATPase to turn it ON
2) Myosin- ADP+Pi is attached to actin= cross-bridge formed
3) Release Pi + ADP from myosin= power stroke
4) ATP binds myosin= release
5) ATP hydrolysis to ADP+Pi= new cross-bridge formed
What is the result of decreased MLCK activation?
Relaxation
What causes relaxation in smooth muscle?
1) Intracellular Ca++ decreases, preventing MLCK activation & necessary phosphorylation/ activation of Myosin ATPase
2) Dephosphorylation of myosin by myosin phosphatase
How does the neural regulation of smooth muscle differ from skeletal muscle?
- No structural neuromuscular junction like in skeletal muscle
- Diffuse branches of nerves overlie smooth muscle
- Multiple varicosities along the nerve fiber instead of end feet
- Increased space between varicosity & muscle fibers
Define electromechanical stimulation.
- Change in membrane permeability resulting in depolarization of smooth muscle
I.e. opening Na+ &/or Ca++ membrane channels leading to a depolarization
Define pharmacomechanical stimulation.
- NOT CHANGING MEMBRANE POTENTIAL
- Activation of signaling molecules that through the generation of second messengers activate the contractile process.
E.g. Hormone activates PLC, increasing IP3 & Ca++; increase of intracellular Ca++ causes contraction of smooth muscle
Define electromechanical inhibition.
- Change in membrane permeability that results in hyperpolzarization of smooth muscle
E.g. close Na+ &/or Ca++ channels or open K+ membrane channels.
Define pharmacomechanical inhibition.
- NOT CHANGING MEMBRANE POTENTIAL
- Activation of signaling molecules that through the generation of second messengers inhibit the contractile process.
E.g. Hormone activates PKA that phosphorylates MLCK, preventing Ca++-Calmodulin from binding & activating MLCK
What are the two sources of Ca++ in smooth muscle? Which is the primary source?
ECF= primary SR= secondary
What are the two roles of Ca++ in smooth muscle?
1) Membrane depolarization i.e. influx of Ca++ & Na+ are important for action potential
2) Contraction via the activation of MLCK
What are the two types of action potentials that occur in smooth muscle?
1) Spike potentials
2) Action potentials with plateaus
Draw a spike potential & List the different ions that important for the phases the action potential.
asdf
Draw an action potential with plateau & list the different ions that important for the phases of the potential.
asdf
What are slow wave potentials?
A continuous cycling of depolarization & repolarization without eliciting a spike potential that leads to a contraction.
- Seen in some types of smooth muscle
- Serve as pacemakers for some types of smooth muscle
- An action potential could occur at the peak of the slow wave
*THIS IS NOT AN ACTION POTENTIAL
What causes slow-wave potentials?
Na+ pumping or rhythmic changes in ion conductance
What ion is primarily responsible for depolarization during action potentials in smooth muscle?
Ca++
*Note that Na+ does play a role, but Ca++ is primary, like cardiac action potentials.
What ion is responsible for the prolonged state of depolarization seen in action potentials with plateaus?
Ca++
What NT is released from all of the preganglionic fibers?
ACh
*Regardless of system, all preganglionic fibers release ACh
What do the postganglionic fibers of the PNS release?
ACh
What do the postganglionic fibers of the SNS release?
NE/Epi or DA
What is the exception to postganglionic fibers of the SNS releasing NE/Epi or DA?
Thermoregulatory sweat glands, which posses muscarinic receptors & respond to ACh
What neurotransmitter do postganglionic fibers to the renal vascular smooth muscle release?
DA
What NTs are released by the adrenal medulla?
Epi & NE
What receptors are present in the target organs of the PNS?
Muscarinic ACh
What receptors are present in the thermoregulatory sweat glands?
Muscarinic ACh
What receptors are present in the target organs of the SNS? What are the two exceptions to this?
- Alpha & Beta Adrenergic
- Exceptions: 1) thermoregulatory sweat, 2) renal vasculature
What receptors are present in the renal vasculature?
DA-1
What receptors are present in skeletal muscle?
Nicotinic ACh
How is ACh synthesized?
1) Uptake of choline from the ECF via the Na+ dependent choline transporter (CHT)
2) Conjugation by ChAT (AcetylCoA + Choline)
3) Final product: ACh
Note that acetylcholine is synthesized in BOTH the cytoplasm & in the mitochondria. ChAT= choline acteyltransferase
What drug can block the choline transporter (CHT)?
Hemicholiniums
*Note that these are not used clinically.
How is ACh stored?
Once ACh is synthesized, it is transported into the storage vesicle via the “vesicle assocaited transporter” (VAT)
What drug blocks VAT?
Vescamicol
How is ACh released?
1) Depolarization of nerve
2) Voltage-dependent Ca++ entry
3) Ca++ binds Calmodulin, activating “vesicle associated membrane proteins,” VAMPs & “synaptosome-assocaited proteins,” (SNAPs)
4) Exocytosis
What is the function of the VAMPs & SNAPs?
Docking storage vesicles on the inner surface of the nerve terminal facing the synapse
- Fusion of the synaptic vesicle with the neural membrane
What does botulinum toxin block?
VAMPs & SNAPs
*Botulinum toxin enzymatically removes two amino acids from one or more of these fusion peptides
How is ACh action terminated?
1) Rapid hydrolysis of ACh via acetylcholine esterase (AChE)
2) Choline re-uptake into terminals
3) ACh interaction with ACh autoreceptors
What does acetylcholine esterase break ACh into?
Choline & Acetate
What drug blocks Acetylcholine esterase? What happens at the synapse in response to these drugs? Give an example of an AChE inhibitor.
- AChE inhibitors
- Increase ACh concentrations & over-stimulation of receptors
*Neostigmine is an AChE inhibitor
What are the two major types of ACh receptors?
- Muscuarinic
- Nicotinic
What are muscarinic receptors?
Transmembrane G-protein coupled receptors
*The type of G-protein associated with the particular receptor will result in a differential effect
What are nicotinic receptors?
Transmembrane Na+ ion channel
*ACh acts as a ligand that causes the channel to undergo a conformational change & opening when bound; both Na+ & K some K+ flow down their electrochemical gradients
What type of alpha subunit is associated with M1 & M3? What does their activation ultimately lead to?
- Gq
- Increased Ca++
- Increased PKC
What type of alpha subunit is associated with M2? What does the activation of M2 ultimately lead to?
- Gi/o
- Decreased cAMP
- Decreased PKA
What muscarinic receptors are present in the heart? What nervous system are they associated with?
- M2
- PNS
What type of G-protein is associated with the M2 receptor in the heart?
Gi/o= inhibitory G-protein
Decrease cAMP & PKA
What do M2 receptors inhibit in the heart?
- SA node= negative chronotrope
- AV node= decreased conduction velocity
- Atrial muscle= decreased atrial contracion
- Ventricular muscle= decreased ventricular contracion
What type of muscarinic receptor is present in the lungs?
M3
What is the effect of M3 activation in the lungs?
- Contraction of the bonchi & bronchioles
- Secretion from submucosal glands
*DO NOT use drugs in asthma patients that have PNS activity
What type of muscarinic receptor is present in the stomach? What is the effect of stimulation of these receptors?
M3, motility & cramps