Block 4 Flashcards
Endocrine signaling
Cells release signals that travel long distances to other cells
What is an example of endocrine signaling?
Insulin released from pancreatic beta cells stimulates glucose uptake
Paracrine signaling
Cells release signals that affect nearby target cells
What is an example of paracrine signaling?
- Vascular endothelial cells secrete vasodilators/constrictors, prothrombotics, etc.
- Tumors promote angiogenesis via paracrine signalling of VEGF etc.
Juxtacrine signaling?
Cells communicate with the cell right next to it with membrane-bound molecules (requires cell to cell contact)
What is an example of juxtacrine signaling?
Axons growth and migration is dependent on juxtacrine signaling with its substrate
Autocrine signaling
The signal and response are generated from the same cell
What is an example of autocrine signaling?
Many squamous cell carcinomas secrete VEGF or EGFR to stimulate their own growth through autocrine signaling
Intacrine signaling
A molecules synthesized by the cell stimulates an intracellular receptor; ie signaling within the cell
What is an example of intacrine signaling?
Some breast CA cells can produce their own estrogen that stimulates growth via their own intracellular receptors
ACh
Binds to nicotinic receptor at the NMJ:
ACh -> Na+ -> depolarize -> DHP receptor (linked to ryanidine receptor) -> Ca2+ influx from SR -> contraction
GalphaS protein
G coupled protein activated by epi:
Epi -> beta adrengergic receptor -> GalphaS -> adenylate cyclase -> ATP to cAMP -> cAMP dependent protein kinase A -> phosphorylates -> changes cell function
GalsphaQ protein
G coupled protein activated by norepi:
Norepi -> alpha adrenergic receptor -> GalphaQ -> phospholipase C -> IP3/DAG -> Ca2+/activated protein kinase C -> calmodulin dependent protein kinase
What effect do cholera toxin (CT) and E coli toxin (ETx) have on cell signaling?
CT and ETx activate proteins downstream of stimulatory GPCR which causes constitutive activation of adenylate cyclase and rapid elevation of cAMP
How does pertussis toxin (PT) affect cell signaling?
PT inhibits a cAMP inhibitor also leading to constitutive activation of cAMP
Which hormones use intracellular nuclear receptors
Retinoic acid, Vitamin D, thyroid hormones, steroid hormones
Tamoxifan
Estorgen analog that does not stimulate growth veing investigated as CA tx
Guanylyl cyclase
Synthesizes cGMP
Adenylate cyclase
Synthesizes cAMP
NO
Diffuses through the membrane and activates the soluble form of guanylyl cyclase to affect smooth muscle contraction and neurotransmission
How does viagra work?
Viagra inhibits PDE5, a phosphodiesterase that breaks down cGMP; this relaxes (ie vasodilates) vascular smooth muscle and produces an erection
Tropomyosin
Blocks myosin binding site on actin to inhibit muscle contraction
Troponin C
Displaces the tropomyosin-actin complex when bound with Ca2+ so that myosin can bind and the muscle can contract
What is the function of structural muscle proteins?
Transmit movement or force to the outside of the cell as well as maintain sarcomere structure
What is the function of motor muscle proteins?
Turn the motor “on” in muscle
What is the structure of muscle myosin II?
Hexamer with a helical coiled coil chain w/ two heavy chains that each have a regulatory light chain and an essential light chain
What type of filaments does the A band contain?
Mostly thick filaments
What type of filaments does the I band contain?
Mostly thin filaments
What happens at the Z disk?
Actins attache
What structural proteins does skeletal muscle contain?
Titin, nebulin, M-line proteins, Z-disk proteins (alpha-actinin, cap-Z, 7 others), actin (connects Z disks), focal contact proteins (adherens junctions, focal adhesions), and extracellular proteins (collagen, elastin)
What are the 3 filaments in a sarcomere?
Thick filaments (myosin), thin filaments (actin, tropomyosin, troponin), titin
What does titin do?
Titin keeps myosin filaments centered during contraction, acts as a molecular ruler during myogenesis, and is involved in passive-length tension
What is passive length tension?
D/t muscles’ structure, it is able to produce some tension even when it is not contracting
What is muscular dystrophy?
These are a group of disorders involving missing proteins in the dystrophin-glycoprotein complex which leads to weak contractions, disrupted membranes, and elevated ion fluxes
What is titin attached too?
Titin is links the Z line to the thick filament
M line
Located in the middle of the A band and vertically connects thick filaments
Cap Z proteins
Cap the ends of thin filaments on the Z band
What determines the speed of muscle contraction?
The rate of product release, ie rated of Pi release
Slow twitch fibers
Type I fibers; small fatigue resistant, run on glycogen and have high mitochondria/low glycogen content and red myosin
Fast twitch type II A fibers
Intermediate-sized fatigue resistant fibers w/ red myoglobin, high mitochondria content, abundant glycogen, and oxidative metabolism
Fast twitch type II B fibers
Large-sized fatigable fibers w/ white myosin, few mitochondria, abundant glycogen, and glycolytic metabolism
Familial hypertrophic cardiomyopathy (HCM)
Single amino acid mutation usually affecting the myosin heavy chain that alters ATP hydrolysis/force production and leads to ventricular wall hypertrophy; leading cause of sudden cardiac arrest in young adults
Endplate potential
Transient depolarization d/t ACh binding at the NMJ which then becomes an AP
T tubules system
Invaginations of the sarcolemma that faciliates rapid Ca2+ release after receiving an AP
Malignant hyperthermia
Genetic mutation affecting RyR1 where uncontrolled muscle contraction is triggered by exposure to anesthetics and/or depolarizing neuromuscular blockers
RyR-2 defects
Decreased numbers of RyR-2 in cardiac muscle leads to decreased energy expenditure, hypertrophy and heart failure
Troponin complex`
Ca2+ regulating protein w/ 3 subunits found in striated muscle (ie skeletal and cardiac but not smooth)
Troponin-T subunit
Binds tropomyosin
Troponin-I subunit
Inhibitory
Troponin-C subunit
Ca2+ binding
How does elevated Ca2+ concentration effect troponin?
At high concentrations, Ca2+ binds to troponin C which allows for Pi dissociation and consequent power stroke
How does low Ca2+ concentration effect troponin?
At low concentrations, steric hindrance inhibits Pi release so there is no power stroke
Lusitrophy
Myocardial relaxation
How is cardiac troponin different from skeletal muscle troponin?
It has a serine residue that becomes phosphorylated during sympathetic activation which leads to decreased Ca2+ sensitivity, causing it to leave the troponin complex more rapidly which ultimately contributes to lusitrophy. Also cardiac troponin is longer
Which step of cardiac muscle contraction is regulated?
The power stroke (ie dissociation of Pi)
What kind of muscle produces the greatest force?
Smooth muscle d/t increased number of cross bridges
How are thick filaments regulated in smooth muscle?
Phosphorylation turns thick filaments on via activation of MLCK or activation of ROK
Myosin light chain kinase (MLCK)
Activated by Ca2+ induced calmodulin; phosphorylates myosin to turn it on and cause muscle contraction
Myosin light chain phosphatase (MLCP)
Dephosphorylates the the light chain to turn the thick filament off in smooth muscle
Rho A kinas (ROK)
Ca2+ independent inhibitor of MLCP that turns thick filaments on in smooth muscle
How does smooth muscle generate high force
Myosin is kept in a tight binding state d/t the slow rated of ADP release after the power stroke
Caldesmosome and calponin
Ca2+ sensing proteins in smooth muscle; turn thin filaments on if there is increased Ca2+ concentration which allows for muscle contraction if the MLC is phosphorylated
How does smooth muscle relax?
Smooth muscle relaxes when there is no stimulus
How does cGMP effect smooth muscle?
cGMP stimulates cGMP phosphodiesterases which lower intracellular Ca2+ and activate MLCP, which relaxes smooth muscle and increases blood flow
How is the force of muscle contraction related to Ca2+ concentration?
The force of muscle contraction is directly proportional to Ca2+ concentration
Motor unit
All of the myofibers innervated by a single motor neuron
Choline acetyltransferase (CAT)
Catalyzes the synthesis of ACh in the presynaptic terminal
How is the generation of APs different in skeletal muscle vs neurons?
D/t post-junctional folds of the skeletal muscle membrane w/ ACh receptors and vesicles all lined up, each release of neurotransmitter will generate an AP whereas in neuroaxo-dendrite synapes, many neurotransmitter releases is required to produce an AP
How are neurotransmitters released from motor neurons?
An AP travels down the axon of a motor neuron which depolarizes the membrane and opens voltage-gated Ca2+ channels which then stimulates transmitter release
What kind of ACh receptor do skeletal muscles have?
Nicotinic ACh receptors
Dihydropyridine receptors (DHP)
An L-type Ca2+ channel in the T tubules that is physically linked to the ryanodine receptor; allows Ca2+ to diffuse into the cell following depolarization at the NMJ
Calsequestrin
Ca2+ binding protein that pulls Ca2+ out of solution so SERCA can transport it back to the SR
Myasthenia gravis
Autoimmune dz in which Abs are produced against the ACh receptor. Can be tx’ed with ACh esterase inhibitors that increases the concentration of ACh in the NMJ
What are the two types of smooth muscle?
Single-unit and multi-unit
Where is multi-unit smooth muscle found?
Ciliary muscle in the eye, piloerector muscles
Where are single-unit smooth muscles found?
Organs of viscera requiring coordinated contraction
What is the function of gap junctions in smooth muscle?
Gap junctions are found in single-unit smooth muscle where they facilitate coordinated contraction by allowing ions to flow from one cell the the next; ie they allow the cells to function as one just like cardiac muscle
Where does skeletal muscle get Ca2+ from?
Intracellular stores it the SR
Where does smooth muscle get Ca2+ from?
Intracellular or exracellular sources (through v-type Ca2+ channels)
What does ACh do in smooth muscle?
ACh from parasympathetic neurons activates the muscarinic receptor in smooth muscle to cause muscle contraction via the PIP and IP3 pathway
What does norepi do in smooth muscle?
Norepi from sympathetic neurons activates beta adrenergic receptors which causes smooth muscle relaxation
What are some endocrine regulators of smooth muscle?
Oxytocin, CCK, api, angiotensin II
What are some paracrine regulators of smooth muscle?
NO, oxygen, prostaglandins, histamine
How does NO decrease bp?
NO diffuses across the membrane (bc it is a gas) and stimulates cGMP, which stimulates protein kinase G, which then decreases muscle contraction and lowers bp
Endothelial nitric oxide synthase (eNOS)
Stimulated by increased Ca2+ which then synthesizes NO and causes smooth muscle relaxation; ie increases Ca2+ can also have vasodilator effects
What effect do stretch-activated channels have on smooth muscle?
Stretch-activated channels open v-type Ca2+ channels which cause muscle contraction
Protein kinase A
Activated by cAMP via the epi-GalsphaS signaling pathway
Protein kinase C
Activated by DAG via the norepi-GalphaQ signaling pathway
How does the PNS regulate smooth muscle?
The PNS stimulates contraction of smooth muscle by releasing ACh which binds to muscarinic receptors and initiates the GalphaQ signaling pathway
How does the SNS regulate smooth muscle?
The SNS can stimulate contraction via norepi binding to to beta adrengergic GalphaS receptors and initiating the adenylate cyclase/cAMP pathway or it can stimulate relaxation by binding to the GalphaS alpha receptor
What is the function of cGMP in smooth muscle?
cGMP (stimulated by NO) activates protein kinase G which decreases intracellular Ca2+ and thus inhibits muscle contraction
Protein kinase G (PKG)
PKG decreases intracellular Ca2+ in smooth muscle either by inhibiting mobilization from intracellular stores or by inhibiting its import from extracellular stores
How are smooth muscle APs different from skeletal muscle APs?
Smooth muscle has relatively few Na+ channels and the upswing of the AP depends on Ca2+ rather than Na+ (many smooth muscle just exhibit graded depolarizations rather than APs)
What is the role of voltage gated K+ channels in smooth muscle?
Activated K+ channels hyperpolarize the cell, close Ca2+ channels and inhibit contraction/vasodilate. Closed K+ channels depolarize the cell, open Ca2+ channels, and contract/vasoconstrict smooth muscle
Where does smooth muscle in the gut receive input from?
Stretch activated channels, blood-borne ligands (hormones), autonomic neurons, enteric neurons, inflammatory cells releasing NO
ICC
Pacemaker cells in the gut
What effect do catecholamines have on cardiac muscle?
Catecholamines bind to the GalphaS beta receptor and initiate the adenylate cyclase/cAMP pathway. This actiavtes phospholamban which activates the Ca2+ channel in the SR
Phospholamban
Opens the Ca2+ channel in the SR after binding of catecholamines to the GalphaS beta receptor on cardiac muscle
What is the sequence of smooth muscle contraction?
Ca2+ -> binds calmodulin -> binds MLCK -> phosphorylates myosin -> increases rated of actomyosin ATP hydrolysis -> contraction
Multi-unit smooth muscle
Each unit is capable of contracting individually
Single-unit smooth muscle
Arranged in tight contact with each other and connected by gap junctions so that contracts will be coordinated
Time constant
The length if time it takes for a signal to propagate; the larger the time constant, the longer it takes to propagate
How do K+ channel blockers tx sxs of MS?
Blocking K+ channels prolongs the AP
How do local anesthetics work?
Block Na+ channels so sensory neurons don’t fire
When does the power stroke of the cross bridge cycle occur?
After the loss of Pi but before the loss of ADP from the myosin head
Titin
Protein that attaches the Z line to the thick filament and is responsible for much of the passive force produced in skeletal muscle
Alpha-actinin
Protein found in both Z disks and dense bodies of smooth muscle
Saltatory conduction
Propagation of APs along myelinated axons
Active force
Proportional to the number of cross bridges
