1-cardio Flashcards
what is Ca2+ important for
contraction
excitation
secretion
what happens with high intracellular ca2+
cytotoxic (hypercontraction)
what is the concentration of cytosolic (intracellular) calcium
100nM (10^-7 M)
what is the concentration of extracelluar calcium
2mmolM (2.5^-3 M)
where is calcium stored
ER and SR and mitochondria
what are calcium sparks
localized release of intracellular calcium stores
what are 5 calcium entry mechanisms
ligand gated,
voltage gated,
store operated calcium channels, GPCRs, and ryanodine receptors
when do voltage gated ca channels open
when cell is depolarized
what are the types of voltage gated ca channels
LNPRT (Cav1=L, Cav2= NPR, cav3=T)
where are N and P calcium channels and what do they do
neuronal and invovled in NT release
where are L type calcium channels
heart and smooth muscle
name 3 voltage gated Ca2+ inhibitors
verpamil
diltiazem
dihydropyridines (nifedipine)
what does verapamil do
block voltage gated calcium channels
what are dihydropyridines? give an example
type of voltage gated Ca2+ channel blocker
nifedipine
what does nifedipine do
type of dihydropyridines, blocks voltage gated Ca2+ channels
what is diltiazem?
inhibitor of voltage gated Ca2+ channels
what are verapamil, diltiazem and dihydropyridines (nifedipine) used for?
angina hypertension and some cardiac dysrhythmias by reducing contraction of vascular smooth muscle
what is an example of a highly permeable Ca ligand gated channel
NMDA glutamate channels
what can be an issue with ligand gated channels
can cause so much Ca2+ entry the cell dies
what are ATP-gated P2X channels?
only true ligand gated ion channel in smooth muscle, very calcium permeable
what type of channel is the CRAC channel
store operated calcium channel
what does CRAC channel stand for
calcium release activated channel
how do SOC and CRAC increase intracellular store (mechanism)
Depletion of Ca(2+) from the ER causes STIM (calcium sensing proteins) to accumulate at ER-plasma membrane (PM)
-physical interactions allows CRAC channels to open
what are 3 calcium extrusion mechanisms
PMCA (plasma membrane calcium ATPase)
NCX sodium calcium exchanger
SERCA (sarcoplasmic endoplasmic reticulum calcium ATPase)
what does Ca2+ ATPase get energy from
why does it need energy
atp hydrolysis (transport across concentration gradients)
what does the plasma membrane PMCA pump do
keep cytoplasmic Ca2+ low by pumping it out of the cell (type of Ca2+ ATPase)
what does the SERCA pump do
keep cytoplasmic Ca2+ low by pumping it into ER or SR (type of ATPase)
what does thapsigargin do
block SERCA pump, can cause contraction due to increased intracellular calcium)
what does the NCX Na-Ca exchange do (which molecules how many and where)
brings 3 Na+ in and 1 Ca2+ out
how does NCX get energy
couples the flow of 3 Na+ ions down their EC into the cytosol to the move 1 Ca2+ ion out of the cell against its concentration gradient
where is the NCX
on plasma membrane
where is PMCA
on plasma membrane
why can NCX cause depolarization?
the transporter is elecrogenic (it causes the net movement of 1 positive charge inward, since it moves 3 Na+ in and 1 Ca2+ out)
describe reverse mode NCX activity
caused by a reduction in the Na+ concentration gradient
if the concentration of Na+ in the cell is too high, it will action case Na+ to leave the cell and bring Ca2+ in
what are 2 transporters that do exchange between ER SR and cytosol
inositol tris phosphate receptor (GPCR)
ryanodine receptor (calcium induced calcium release)
what does the IP3 receptor do
ligand gated ion channel in the SR/ER that is activated by IP3
results in activation of Gq signalling and elevation of intracellular calcium (and DAG –> PKC)
what does RYANODINE do
activates RyR at low concentrations (nanomolar) but closes them at high concentrations (micromolar)
what kind of ryanodine receptor is involved in skeletal muscle contractions
RyR1
what kind of ryanodine receptor is involved in cardiac muscle contractions
RyR2
what does ryanodine receptors do to ca2+ release in cardiac muscle? mechanism?
CICR (calcium induced calcium release)
Ca2+ acts on RyR to release Ca2+ from the ER/SR
what does CAFFEINE do?
sensitizes ryanodine receptor and causes Ca2+ release from ER SR at physiological Ca2+ concentrations
sensitizes muscle to contract more
stimulant
what does dantrolene do
what is it similar to
blocks RyR (like ryanodine does at high conc)
what is dantrolene used for
malignant hyperthermia caused by genetic RyR abnomalities or anesthesia
mutations cause RyR to be oversensitive, resulting in too much intracellular calcium, too much heat release and hyperthermia
what is calmodulin
ca binding protein that activates many effectors
what is the main downstream effector for calmodulin
CaM kindase
calcium calmodulin kinase
what are some molecular targets for ca
enzymes kinases phosphatases transcription factors synaptic vesicle proteins (NT release) contractile proteins ca binding proteins as intermediate ca sensitive ion channels
Is na higher on inside or outside
outside
Is k higher on inside or outside
inside
Is Cl higher on inside or outside
varies, but higher outside
what determines resting membrane potential
resting K channels (selectively K permeable)
what is the normal resting membrane potential determined by K+
-40 to -80 mV
which three ion pumps are primarily responsible for controlling ion concentrations within the cell?
NaK ATPase and Ca ATPase and NCX)
does Na K pump cause hypo or hyper polarization and why
hyperpolarization because it makes the inside more negative (3 na out 2 k in)
what does digoxin do and what is its drug class
digitalis cardiac glycosides, blocks Na K ATPase
what happens in action potential (2 main things)
threshold stimulus causes opening of voltage gated Na+ channels, rapid influx of Na+, followed by inactivation of Na+ channels and delayed outward flux of K+ results in repolarization
what causes the refractory period
inactivation of Na channels
is the AP and depolarization mechanism same in all tissues
no, varies per tissue. complex in heart
what do drugs that cause depolarization do to excitability
increase
what do drugs that cause hyperpolarization do to excitability
decrease
what does a stronger depolarizing stimulus do to AP
increases # of them
what is the classical pharmacology method of seeing drug effects of muscle contraction
take contractile tissue and put into organ bath
add drug
monitor contractions with transducer
what causes contraction of muscle
interaction between actin and myosin fueled by ATP and initiated by increase in intracellular Ca
interaction is inhibited, by troponin, MLCK
what does ACh at nAChR do
causes depolarization (excitatory junction potential)
decribe the steps of skeletal muscle contraction
ACh activated nAChRs, resulting in depolarization
AP propogates thru T-tubules, activating L-Type Ca2+ channels (aka dyhydropyridine receptors)
Mechanical stimulation of RyR1 receptors on the ER/SR, causing Ca2+ release
Ca2+ release binds troponin, removing it from myosin binding site on actin
Muscle contraction!
what happens when L-type dihydropyridine ca receptors are activated in skeletal muscle
RyR1 receptors on adjacent ER/SRcome close to L-type dihydropyridine ca receptors to activate Ca release
what 2 receptors need to be together to cause ca release in skeletal muscle
L-type dihydropyridine ca receptors and RyR1
what happens in skeletal muscle once ca is release
ca binds to troponin
what does troponin do
stops interaction between actin and myosin
what happens when ca binds to troponin
stops troponin blocking interaction by actin and myosin so that you can have contraction
what kind of tissue is myogenic and what does it mean
heart because it does not need stimulus to start contraction
describe cardiac muscle contraction
Change in voltage results in opening of L-type Ca2+ channels
Ca2+ causes activation of Ryr2 to release Ca2+ from the ER/SR
CICR
Contraction!
what receptor in heart is activated by AP
L-type Ca2+ receptors (voltage gated)
what happens when L-type ca receptors are activated in heart (2 things)
releases ca
and that ca activates RyR2 to release ca from ER SR
describe the difference between skeletal and cardiac muscle contraction
skeletal needs L type and ryanodine to be beside each other
heart doesn’t (L type releases calcium which stimulates RyR)
what makes smooth muscle contraction different than heart and skeletal
no troponin!!!
if smooth muscle lacks troponin, what causes contraction?
myosin light chain kinase
what do agonists working through Gq do to smooth muscle
contract (alpha 1)
what do agonists working through Gs do to smooth muscle
relax (beta 2)
what does NO do to smooth muscle
relax (guanylyl cyclase)
what does cAMP do in the smooth muscle contraction pathway and how?
inactivate MLCK by phosphorylating it (double phosphorylation)
INHIBITS CONTRACTION/CAUSES RELAXATION
what does cGMP do to smooth muscle pathway contraction pathway and how?
dephosphorylating myosin-LC-PO4
INHIBITS CONTRACTION/CAUSES RELAXATION
what does Gq signalling do to smooth muscle contraction and how?
intracellular Ca2+ release –> activated Ca2+ calamodulin –> activate MLCK –> phosphorylated myosin-LC –> contraction
