vgcc
DESCRIPTION
NCE. mM [Ca]. NMDA, AMPA rec. nAChR. CNG. VR/temp rec. VDAC. Stretch receptor. TRP. mM [Ca]. SOC. IP3R. SERCA. 100 nM [Ca]. ROC. VGCC. mM [Ca]. PMCA. RyR. SERCA. Sarcoplasmic Reticulum (SR) / T Tubule System. Twitch. Summation. Tetanus. Role of Ca ++ in contraction. - PowerPoint PPT PresentationTRANSCRIPT
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Why Calcium?
Double positive charge provides increased affinity for negatively charged proteinsbut lower affinity than larger divalent cations such as Cu, Zn, or Mn. Thecoordination chemistry of Ca is higher and more flexible than for Mg.
The fact that Ca complexes with inorganic compounds and to proteins suggeststhat the maintenance of low [Ca] intracellularly would require less energy than forother cations. The maintenance of a large transmembrane gradient is critical fora second messanger ion.
This large transmembrane gradient provides the signal-to-noise ratio required forefficient signal transduction.
Resting intracellular [Ca] is ~100 nM versus mM extracellular [Ca] or aconcentration gradient of ~10,000.
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VGCC
ROC
SOC
TRP
Stretch receptor
CNGnAChR
NMDA, AMPA rec
VR/temp rec
IP3R
RyR
VDAC
SERCA
SERCA
NCE
PMCA
mM [Ca]
100 nM [Ca]
mM [Ca]
mM [Ca]mM [Ca]
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Sarcoplasmic Reticulum (SR) / T Tubule System
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Twitch
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Summation
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Tetanus
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Role of Ca++ in contraction
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SR SR
T-tubule T-tubuleA B
SR
Muscle contraction
T-tubuleVDCC
RyRFKBP12/12.6
Ca release
CRyR Accessory proteinsFKBP12/12.6KinasesPhosphatasesAdaptor/anchoring/targeting proteinsSorcinS100sTriadinJunctinAnnexin VICalmodulin
VDCC
RyR1
RyR2
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vertebrate skeletal muscle contraction
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Excitation-contraction coupling
Ryanodine receptors
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Properties of Calcium Release Channels
Ryanodine Receptors
RyR1 RyR2 RyR3Size (amino acids)
of monomer 5,037 4,970 4,870Size (daltons) of
monomer ~565,000 ~560,000 ~560,000Sedimentationcoefficient of
tetramer30 S 30 S 30 S
Stoichiometry ofFKBP/RyR 4 4 4
Single channelconductancein Ca 50 mM
~120 pS ~120 pS ~100 pS
Single channelconductancein Cs 250 mM
~540 pS ~540 pS ?
Endogenousmodulators
M Ca activates yes yes yesmM Ca inhibits yes yes yesmM Mg inhibits yes yes yes
kinases yes yes ?phosphatases yes yes ?
DHPR interaction yes ? ?calmodulin yes yes yes
adeninenucleotides yes yes yes
MgATP yes yes yesNO yes yes ?
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Pharmacology of Ryanodine Receptors
RyR1 RyR2 RyR3 Site of actionXanthines(caffeine) activates activates activates Ca activation sites
Ryanodine/ryanoids
subconductancestate
subconductancestate
subconductance state
carboxyterminus
ruthenium red inhibits inhibits inhibitsCa binding
site(s)/channelpore
Antraquinones(doxorubicin) activates activates activates ?
FK506 &rapamycin activates activates activates FKBP12/12.6Purinergicagonists/
antagonists(adenosine)
activates activates activates ATP binding sites
Calmodulinantagonist
inhibits inhibits inhibits calmodulin bindingsite
Local anesthetics(tetracaine) inhibits inhibits inhibits ?Dantrolene inhibits inhibits ? ?
Phenol derivatives(4-chloro-m-
cresol)activates activates ? ?
NO generatingcompounds Activates/inhibits Activates/inhibits ? ?
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RyR
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SRMembrane
Cytosol
Lumen
NH2
CO2H5000
4000
3000
2000
1000 500
4500
3500
1500
2500FKBPPP2A
PP1
mAKAPRII-PKA
PKA/CamKIIPO4 siteCalmodulin
Rya
no
din
e
P
Ca-Inactivation
Ca-Activation
GIG
DHPR/RyR1
MH/CCD
MH/CCD
MH/CCD
M1 M2 M3 M4
RyR2
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Voltage-gated ion channels
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RyR2
SR
Lumen
Ca2+
Ca2+
P
P
P
1AR 2AR
AC
cAMP
Regulation of EC coupling by adrenergicsignaling --“fight or flight”
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RyR2 macromolecular complex
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RyR macromolecular complexes are RyR macromolecular complexes are held together byheld together by
leucine/isoleucine zippersleucine/isoleucine zippers
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RyR2/calcium release channel phosphorylated RyR2/calcium release channel phosphorylated by addition of cAMP aloneby addition of cAMP alone
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PKA PKA phosphorylation phosphorylation activates RyR2 activates RyR2
and induces and induces subconductance subconductance
statesstates
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Cytosolic [Ca]
RyR
2 o
pen
pro
bab
ilit
yR
yR2
op
en p
rob
abil
ity
ECC gainCa transientcontractility
DADs - SCD[Ca]
Time
Iso CHF
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IP3R RyR
Skel muscle + +++
Smooth m. +++ +
Neurons +++ +++
IP3 Activates None
Ryanodine None Locks open/closes
Caffeine (5 mM) Inhibits Activates
Ca2+ IP3R1 - biphasic
IP3R2/3 - opens
biphasic
RR None inhibits
Heparin inhibits activates
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Excitation-secretion coupling
Inositol 1,4,5-trisphosphatereceptors
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IP3 Receptors
IP3R1 IP3R2 IP3R3Size (amino acids)
of monomer 2,749 2,691 2,685Size (daltons) of
monomer 313,000 ~300,000 ~300,000Stoichiometry of
FKBP/RyR 4 4 ?
Endogenousmodulators
IP3 activates activates activatesnM Ca activates yes yes yesM Ca inhibits yes yes noATP <2 mM activates activates activatesATP >2 mM inhibits inhibits inhibits
tyrosine kinases activates ? ?phosphatases ? ? ?
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Pharmacology of IP3 Receptors
IP3R1 IP3R2 IP3R3 Site of action(caffeine) inhibits inhibits inhibits Ca activation sitesheparin inhibits inhibits inhibits ?2-APB inhibits inhibits inhibits ?
xestospongin inhibits inhibits inhibits ?
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IP3 signaling
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Stable transfectant Stable transfectant
Jurkat T cells do notJurkat T cells do not
express IP3R1express IP3R1
IP3R1IP3R1
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Activation of IP3-gated CaActivation of IP3-gated Ca2+2+ channel by channel by fynfyn
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Bcl-2
P
Bcl-2Bcl-2
Bcl-2
Rec
Growth Factor
Plasma Membrane
Cytoplasm
PIP2PLC-
IP3ER Bad
P
Degradation
14-3-3
Bcl-xBad
Ca2+
IP3R
CalcineurinSERCA
Ca2+
Cytosolic TF
NuclearTF
Survival
Nucleus
Cell Death
DNADigestion
M M
Akt
Cytoskeletal Breakdown
Cytochrome CCaspases
CAD
Bad
Survival
+ X ?
Calcium signaling during apoptosis Calcium signaling during apoptosis
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VGCC
Stretch receptor
CNGnAChR
IP3R
RyR
VDAC
SERCA
SERCA
NCE
PMCA
mM [Ca]
100 nM [Ca]
mM [Ca]
mM [Ca]mM [Ca]
T-tubule
Sarcoplasmicreticulum
Endoplasmicreticulum
mitochondria