Week 04 Lect. 1 - Autonomic NTs + Sm Muscle Flashcards
Where are the CNS origins of parasympathetic innervation?
Sympathetic?
Parasympathetic:
- Cranial: CNs III, VII, IX, X (Oculom., Facial, Vestib., Vagus)
- Sacral: S2-S4
Sympathetic
- Thoracolumbar: Th1-Th12 + L1-L2/3
Where are the ganglia of the parasympathetic NS?
Of the sympathetic?
Parasympathetic: Near or within target organ
Sympathetic: Near spinal cord (para-/prevertebral ganglia)
How do the pre- and post-ganglionic axons differ in para/sympathetic NS?
Para: Long pre-, short post-
Symp: Short pre-, long post-
What is the preganglionic neurotransmitter for para- and sympathetic NS?
And receptor?
Both systems used acetycholine and a nicotinic acetylcholine receptor (nAChR) for pre-ganglionic transmission.
What is the most common post-ganglionic NT in the PsNS?
And less common ones?
And receptors w/ their general effects?
Transmitter: ACh (or sometimes VIP, NO)
Receptors:
-
Muscarinic ACh Receptors
- M1,3,5 - (Gq >>> InsP3, increased [Ca2+])
- M2,4 - (Gi/o >>> Ad. Cyclase inhibition, cAMP decrease)
What are the most common post-ganglionic NTs in the SympNS?
And their receptors/effects?
Transmitters: Norepinephrine + Acetylcholine
Receptors:
- α1 - (Gq >>> InsP3, [Ca2++] increase)
- α2 - (Gi/o >>> Ad. Cyclase inhibition, cAMP decrease)
- β1-3 - (Gs >>> Ad. Cyclase activation, cAMP increase)
- mAChRs
What are two examples of sympathetic co-transmitters which work with norepinephrine (NE) in the sympathetic NS?
- NE-NPY (Neuropeptide Y) - present in GI vessesl, effect on appetite, etc.
- NE-Somatostatin
How are NTs eliminated from synapses in the parasympathetic NS?
And sympathetic?
Para:
- Acetylcholinesterase
- Choline Reuptake
- Diffusion
Sym:
- Norepinephrine Reuptake (w/ cytoplasmic degradation)
- Diffusion
How is neurotransmitter balance modulated at parasympathetic synapses?
And sympathetic?
Para:
- Blocking transmitter release
- Blocking choline reuptake
- Blocking ACh-ase action
Symp:
- Membrane NE Transporter Inhibition (Cocaine)
- NE > Vesicle uptake inhibition
- NE synthesis inhibition
Information from what 5 main sources is integrated into neurotransmission occuring at autonomic ganglia?
presynaptic neuron reaches ggl. via nACHR
- Peripheral Afferent Signals
- Somatic Afferent Signals to CNS
- Interneurons
- misc. Efferent CNS signals
- Local Reflexes
What endocrine cells also release a common sympathetic neurotransmitter + its analogue?
What is special about these cells’ structure?
What signals this secretion and how does it occur?
Adrenal Medulla Cells
- release epinephrine + norepinephrine
- have the structure of a modified, axonless postganglionic neuron
- thoracic sympathetic innervation signals adrenal medullary release of E + NE into the bloodstream
Where is epinephrine created?
How?
What regulates the relevant enzyme?
- in the adrenal medulla
- via Phenylethanolamine N-methyl Transferase (PNMT)
- adrenal glucocorticoid hormones (cortisol, etc.) increase PNMT activity (resulting in a stress-response positive feedback loop)
What are 4 ways that an organ can be innervated by the two branches of the autonomic nervous system?
Specific examples of each?
-
Innervation by only one division
- vascular smooth muscle (α-1 adrenergic, vasoconstriction)
-
Same target cells, both divisions, opposing effects
- heart rate (Para = M2/4 rcptr > decrease, Symp = β1 rcptr > increase)
-
Different target cells, both divisions, opposing effects
- pupil diameter - para > sphincter, symp > dilator
-
Similar response from both systems
-
salivary glands - secretion from both
- Para > non-viscous, enzymatic
- Sym > viscous, mucinous
-
salivary glands - secretion from both
How are smooth and skeletal muscles similar (3 ways)?
- Thin/Thick Filaments - slide together > contraction
- Both use an ATP Cycle to induce contraction
- [Ca2++]IC regulates contraction
What are smooth muscle cells’ unique properties?
(5)
- Small, uninucleate cells
- Non-striated
- No Z-lines - thin filaments anchor to dense bodies/membrane
- No T-Tubules - sarcoplasmic reticulum present, of variable importance
- Gap Junctions - connect cells for electrochem. comm.
What are the 3 mechanisms for depolarization-mediated intracellular calcium increase in smooth muscle cells?
-
From neighboring cells via gap junctions
- no stable membrane potential
- ex: elect. pacemaker cells (heart nodes, Cajal cells)
-
Neural Stimulation
- NT release
-
Mechanical Stimulation
- mechanoreceptors > mechanosensitive channels
What is the name of the common mechanosensitive phenomenon for smooth muscle cell activation?
And basically how does it work?
Bayliss Effect
- Tissue is stretched
- Mechanosensitive channels open
- Depolarization occurs
- Contraction
How are smooth muscle action potentials different compared to those of neurons?
3 ways
- Smaller amplitude
- Longer duration
- Different ion channels
What are the ion channels associated with each of the different phases in a smooth muscle action potential?
- Depolarization - L-type Voltage-Gated Ca++ Channel
- Repolarization - Voltage-Gated Late K+ Channel
- Plateau - Ca++-Activated K+ Channel
- also Ca++-induced Ca++ channels + Capacitative Ca++-Influx
Describe the relationship btw membrane potential of and generation of force in smooth muscle.
membrane potential has to reach threshold for contraction
⇒ the greater the depolarization, the stronger the force of contraction
What common, important pharmaceuticals act on smooth muscle cells, effecting their AP production?
And what common toxin does not effect smooth muscle APs?
Ca++ Channel Blockers - common blood pressure meds
TTX (tetrodotoxin) - only inhibits Na+ channels
What is the mechanism for intracellular calcium increase in smooth muscles without membrane depolarization?
Briefly, how does it work?
Pharmacomechanical Activation
- Ligand binds α-1 adrenergic receptor
- Intracellular Gq signaling occurs (Phospholipase C > IP3)
- Ca++ released from SR
What are the components of thin myofilaments in smooth muscle?
How is it different from skeletal muscle?
- Smooth muscle-type actin
- Tropomyosin
- no troponin present in SMCs
What are the components of thick filaments in smooth muscle cells?
- Myosin Heavy Chain - complex of 2 heavy chains
- Myosin Light Chain - 2 light chains per heavy chain
- these are different subunits than skeletal muscle
How does increased intracellular Ca++ concentration induce contraction of smooth muscle?
- Calcium binds calmodulin
- Calmodulin complex activates Myosin Light Chain Kinase (MLCK)
- MLCK Phosphorylates Myosin Light Chain
- MLC actin-binding sites become available for binding
What are the 3 main mechanisms of termination of intracellular calcium signaling?
- Membrane Ca++-ATPase - primary active transport of Ca out of cell
- Membrane Na+/Ca++ Antiporter - secondary active transport of Ca out of cell
- SR-Ca++-ATPase - active transport of Ca into the sarcoplasmic reticulum
What is the intracellular calcium-independent mechanism for smooth muscle contraction?
How does this effect de-activation of contraction mechanisms?
How does it effect the calcium-dependent mechanism?
- Rho-GTP (activated by G12/13) activates Rho-Kinase which phosphorylates myosin light chain
- Rho-kinase inhibits MLC-phosphatase, stopping its de-activating effect
- MLCK and Rho-kinase have an additive effect
What are the two messaging molecules which induce smooth muscle relaxation?
What types of signaling increase the concentration of each one?
- cAMP - β2-adrenergic stimulation
- cGMP - NO-dependent activation
How does cAMP induce smooth muscle relaxation?
- activates Protein Kinase A
- PKA phosphorylates Myosin Light Chain Kinase
- MLCK-P has lower Ca sensitivity than unphosphorylated MLCK and is thus inhibited
How does cGMP induce relaxaton of smooth muscle?
- Activates Myosin Light Chain Phosphatase
- Phosphorylates InsP3 Receptors on sarcoplasmic membrane (deactivating it?)
- Inhibits calcium entry into cell
As a review…
considering all the mechanisms for smooth muscle contraction and inhibition, how would a flow chart-type diagram of these mechanisms look?
What are the two types of smooth muscle “units”?
How are they controlled neurally?
Other special features?
Examples within the body?
-
Multi-Unit
- each cell has its own innervation
- contraction controlled by ANS
- ex: tightly regulated functions, internal eye muscles, ductus deferens
-
Single Unit
- nerve innervates multiple cells connected by gap junctions, only modulating activitiy
- contract spontaneously with basal activity
→ pacemaker activity - “slow waves” - innervated by hormones
- ex: GI + vascular
What are the characteristics of smooth muscle cell contraction regarding their…
calcium signals?
ATP requirements?
Actin-myosin cycle + binding?
- Long-lasting intracellular Ca++ signals
- Lower ATP requirements than skeletal muscle
- Slow actin-myosin cycles
- Cross-bridges between actin and myosin
