SFOM - Excitation/contraction, smooth muscle, cell receptors/signaling {2.12-2.14}

What is a sarcomere?

Structural and functional unit of a myofibril, defined as the region between two Z-discs

What is contained in the I-band?

Actin (thin) filament

What is contained in the A-band?

Entire length of myosin (thick) filaments, including the area where actin and myosin overlap

What is the Z-disc?

anchors actin (thin) filaments and connects adjacent sarcomeres

What is the H-zone?

Central part of A-band containing only myosin (thick) filaments, shortens during muscle contraction

What is the M-line?

Middle of H-zone, anchoring point for myosin (thick) filaments, maintains the alignment of the thick filaments during contraction

What are skeletal muscles directly innervated by?

Alpha motor neurons residing in the ventral horn of the spinal cord

What are upper motor neurons?

Control voluntary movement

What are interneurons?

Class of neurons located within the spinal cord that play a crucial role in processing and integrating sensory and motor information

How is acetylcholine released into the synaptic cleft?

Action potential reaches the axon terminal causing voltage gated Ca2+ to open and move into the terminal and binding to vesicles and releasing into the synaptic cleft

What is exocytosis of acetylcholine vesicles facilitated by?

SNARE proteins

What is the effect of acetylcholinesterase inhibition?

Prevents acetylcholine breakdown in the synaptic cleft and duration and intensity of muscle contractions are enhanced

What is the function of acetylcholinesterase?

hydrolyze acetylcholine to rapidly remove it and terminate the signal for the muscle to contract

Which of the following actions would result from acetylcholinesterase inhibition?

Increase acetylcholine concentration in the synaptic cleft

What is Myasthenia Gravis?

muscle weakness and fatigue caused by autoantibodies against nicotine acetylcholine receptors at the neuromuscular junction

What does acetylcholine bind to in the muscle?

Nicotinic acetylcholine receptors

What happens when acetylcholine binds to nicotinic acetylcholine receptors?

Ion channel opens and Na+ rapidly enters the muscle fiber and depolarizing the motor end plate

What is a T-tubule?

Extension of sarcolemma that penetrates the center of the muscle cell, creates a pathway for action potential to travel into muscle fiber

What is the function of the terminal cisternae of the sarcoplasmic reticulum?

Store Ca2+ 

What happens when the action potential of the threshold is reached in the muscle fiber?

Action potential is propagated down the T-tubule causing the influx of Na+ ions

What are dihydropyridine receptors?

L-type coltage-gated Ca2+ channels

What are ryanodine receptors?

calcium receptors that are physically attached to dihydropyridine receptors

What happens when dihydropyridine receptors are activated?

conformational change that triggers the opening of ryanodine receptors causing the release of calcium ions into the cytoplasm from the sarcoplasmic reticulum

After calcium ions flood the cytoplasm what do they bind to in the muscle fiber?

Troponin C

After calcium ions bind to troponin C what happens?

Conformational change in the troponin complex which moves tropomyosin away from the myosin-actin binding site

What happens after the myosin-actin binding site is exposed?

Myosin heads, energized by ATP hydrolysis, attach to actin forming cross-bridges

What happens after the myosin heads attach to actin?

Myosin heads pivot, pulling the the actin filaments toward the center of the sarcomere, power stroke

What happens after the power stroke in muscle fibers?

A new molecule of ATP binds to the myosin head causing it to detach from the actin filament

What happens after a new molecule of ATP binds to the myosin head?

ATP is hydrolyzed which reenergizes the myosin head and returns it to its original position, ready to form another cross-bridge

What is the function of SERCA?

Pump calcium ions from the cytoplasm back into the sarcoplasmic reticulum

Why is SERCA vital in excitation-contraction coupling?

Helps reset the muscle fiber for the next contraction by clearing calcium from the cytoplasm

What is contraction regulated by in smooth muscle?

Calmodulin

What does dysregulation of smooth muscle tone contribute to?

Disorders such as hypertension, asthma and urinary retention

What are the major differences between smooth muscle and skeletal muscle?

No striations, no troponin, no T-tubules

What serves a similar function as T-tubules in smooth muscle?

Caveolae

What do the filaments connect in smooth muscle?

Dense bodies

Where are gap junctions found in smooth muscle?

single-unit smooth muscle

Why do single-unit smooth muscle use gap junctions?

One autonomic neuron that need gap junctions to propagate and contract as a unit

What does my myogenic mean?

Capable of spontaneous rhythmic contractions, used to describe single-unit smooth muscle

Where is single-unit smooth muscle found?

GI tract, uterus, bladder, small blood vessels

What are multi-unit smooth muscles?

Cells have individual synaptic input and does not have gap junctions

What does neurogenic mean?

Requires nerve stimulation to contract, not spontaneously, used to describe multi-unit smooth muscle

Where are multi-unit smooth muscle found?

Iris, ciliary muscles, large airways, large capillaries, arrector pili

What are autonomic varicosities?

Small swellings/enlargements that can influence many smooth muscle cells at once

What is tonic smooth muscle?

Maintains continuous, sustained contractions for extended periods

What is phasic smooth muscle?

Contracts and relaxes rapidly in response to stimuli

Where is phasic smooth muscle found?

GI tract (peristalsis), urinary bladder (voiding), uterus during labor, ureters

Where is tonic smooth muscle found?

Blood vessels, sphincters, iris of the eye,, airway smooth muscle

What are the two sources of extracellular Ca2+?

Voltage gated L-type Ca2+ channels, store-operated Ca2+ channels (SOCs)

What are store-operated Ca2+ channels (SOCs) activated by?

depletion of sarcoplasmic reticulum stores

How does sarcoplasmic reticulum release Ca2+ in smooth muscle?

IP₃ binds to ligans gated Ca2+ channel in the sarcoplasmic reticulum

What happens when the sarcoplasmic reticulum is depleted in smooth muscle?

SOC channel is opened allowing for influx of Ca2+ from the ECF

What activates protein kinase C (PKC)?

DAG

What gets phosphorylated by MLCK in smooth muscle?

LC₂₀

What are the steps in smooth muscle contraction?

Calcium influx→calmodulin activation→MLCK activation→myosin light chain phosphorylation→cross-bridge cycle intiation

What is the function of the Ca2+-calmodulin complex (CaM)?

Activates myosin light chain kinase (MLCK)

What senses increased Ca2+ in skeletal muscle?

Troponin

What senses increased Ca2+ in smooth muscle?

Ca2+-calmodulin complex (CaM)

What is the latch state in smooth muscle contraction?

enables sustained contraction with minimal ATP consumption through slow cross-bridge cycling where some myosin heads remain attached to actin for prolonged periods

How is the latch state achieved in smooth muscle?

Ca2+ levels fall and mysoin light chain phosphatase (MLCP) becomes more active than MLCK and balance shifts towards dephosohorylation

T/F: myosin heads can remain attached to actin even after dephosphorylation.

True

What is the Ca2+ ATPase (PMCA)?

moves calcium from the ICF to ECF in smooth muscle

What is the Ca2+/Na+ exhanger (NCX)?

exchanges 1 calcium from ICF for 3 Na+ from the ECF and then Na/K pump pumps out sodium (secondary active transport)

What is the function of SERCA pump in smooth muscle?

Moves calcium into the sarcoplasmic reticulum

How can SOCC be used in smooth muscle relaxtion?

SR can still send signals to SOCC if it is empty when trying to refill calcium stores

What are the steps of smooth muscle relaxation?

Decrease in intracellular calcium→Inactivation of myosin light chain kinase(MLCK)→activation of myosin light chain phosphatase(MLCP)→relaxation

What happens when Ca2+ dissociates with calmodium?

Calmodulin becomes inactive which deactivates MLCK

What is the function of protein kinase G (PKG) in smooth muscle?

relaxation because MLCP is activated

What is the function of protein kinase C (PKC) in smooth muscle?

contraction because MLCP is inhibited

What is the function of ROCK (Rho-kinase) in smooth muscle?

Contraction because MLCP is inhibited

What is the pathway of protein kinase G (PKG) via NO?

NO production→NO diffusion→Guanylyl cyclase activation→cGMP production→PKG activation→MYPT1 phosphorylation→MLCP activation→LC₂₀ dephosphorylation→relaxation→PDE5 breaks down cGMP

What is the function of nitroglycerin in the protein kinase G (PKG) pathway?

Nitroglycerin converts to NO and used in patients with Angina

What is the function of viagra in the protein kinase G (PKG) pathway?

PDE5 inhibitor which increases cGMP used in patients with erectile dysfunction

What is the function of PDE5 in the PKG pathway?

breaks down cGMP back to GMP to end the signal

What is the protein kinase C (PKC) pathway?

Ligand binding→PIP₂ hydrolysis→DAG activates PKC→CPI-17 phosphorylation→MLCP inhibition→MLCK activity dominates→Increased LC₂₀ phosphorylation→enhanced contraction

What is the function of DAG in the PKG pathway?

Activates PKG to phosphorylate CPI-17

What is the ROCK (Rho-kinase) pathway?

Ligand binding→RhoA activation→ROCK activation→MYTP1 phosphorylation→MLCP phosphorylation→balance shifts toward phosphorylation→increased LC₂₀ phosphorylation→Ca2+ sensitization and enhanced contraction

Why are the PKC and ROCK pathways highly clinically relevant?

Increase smooth muscle contraction without increasing Ca2+ levels

What are activator cell receptors?

Can bind to ion channels spanning the plasma membrane, causing an alteration in the channels conductance

A 55 year old man presents to the office with difficulty maintaining an erection despite his strong desire for sexual intercourse with his wife. He denies depressed mood or marital difficulties. Past medical history reveals type 2 diabetes mellitus, which was diagnosed 30 years ago. He is started on appropriate drug therapy. Which of the following is most likely to be increased as an effect of this patients new medication?

Intracellular cGMP

A 66 year old male with a past medical history of hyperlipidemia presents with acute onset of chest discomfort while mowing his lawn with a push mower. The pain lasted for approximately 5 minutes, radiated to the jaw, and was relieved with rest. The fastest pharmacological relief for the patients chest pain acts to? 

Activate MLCP

What is the general mechanism of calcium channel blockers in smooth muscle?

Decrease calcium entry into smooth muscle

What is the general mechanism of PKC/ROCK inhibitors in smooth muscle?

Block PKC/ROCK from inhibiting MLCP

What is the net effect on LC₂₀ of calcium channel blockers in smooth muscle?

Decreased phosphorylation due to less MLCK activity

What is the net effect on LC₂₀ of PKC/ROCK inhibitors in smooth muscle?

Decreased phosphorylation due to more MLCP activity

What is a heptathelical cell receptor?

Receptors spanning the plasma membrane and are functionally coupled to intracellular G proteins

What are transmembrane receptors?

activated extracellularly and causes intracellular changes by activating or inhibiting enzymatic intracellular domain

What are cytoplasmic or nuclear receptors?

receptors inside the cell that react to signals that diffuse to interact with them

What are the two classes of ligand-gated channels?

EPSPs and IPSPs

What is the function of ligand-gated channels?

depolarization/hyperpolarization

What is the function of G-protein-coupled receptors (GPCRs)?

Change in [Ca2+] protein kinase activity

What is the function of enzyme linked receptors and nuclear receptors?

Gene transcription/protein synthesis

What is the fastest class of receptor?

Ligand-gated channels

What is the slowest class of receptor?

nuclear receptors

a 34-year-old woman presents to the neurology clinic with a history of progressive muscle weakness and fatigue over the past several months. She reports difficulty in performing daily activities that require muscle strength, such as lifting objects, climbing stairs, and even speaking for extended periods. What type of muscle is most likely effected?

Skeletal muscle, voluntary

a 34-year-old woman presents to the neurology clinic with a history of progressive muscle weakness and fatigue over the past several months. She reports difficulty in performing daily activities that require muscle strength, such as lifting objects, climbing stairs, and even speaking for extended periods. What class of receptor is most likely effected?

Ligand-gated ion channels

What is the function of GABA and Glycine in ligand-gated ion channels?

Hyperpolarization (inhibition)

What is the function of acetylcholine, glutamate and 5-HT₅ in ligand-gated ion channels?

Depolarization (excitation)

a 42-year-old female presents to the emergency department with a sudden onset of severe headaches, palpitations, and profuse sweating over the past few days. She describes these episodes as paroxysms of intense fear and anxiety. What class of proteins are most likely effected?

G-protein-coupled receptors

What is the general activation cascade for GPCRs?

Hormone binds to GPCR→G protein dissociates from the receptor→G protein stimulates a downstream effector