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

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

Excitation-secretion coupling

Inositol 1,4,5-trisphosphatereceptors

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 yesμ M Ca inhibits yes yes noAT <P 2 mM activates activates activatesAT >P 2 mM inhibits inhibits inhibits

tyrosi nekinases activates ? ?phosphatases ? ? ?

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 ?

IP3 signaling

Stable transfectant Stable transfectant

Jurkat T cells do notJurkat T cells do not

express IP3R1express IP3R1

IP3R1IP3R1

Activation of IP3-gated CaActivation of IP3-gated Ca2+2+ channel by channel by fynfyn

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

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