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CaCa2+2+ signallingsignalling in in healthhealth and and diseasedisease
Martin Hohenegger
Center for Physiology and Pharmacology
Institute of Pharmacology PhD-program
Pharmakologisches Institut der Medizinischen Universität Wien
CaCa2+2+freefree 1010--77 MM
CaCa2+2+free
10-3 M
CaCa2+2+free 10-3 M
InsP3cADPrNAADPCa2+
Depol.
Receptors
Ion channels
CaCa2+2+ distributiondistribution in and in and aroundaround cellscells
EncodingEncoding a Caa Ca2+2+ signalsignal
Amplitude decoded
Fequence decoded
EncodingEncoding a Caa Ca2+2+ signalsignal
SequentialSequential calciumcalciumamplificationamplification signalsignal
Blip/QuarkBlip/Quark: single channel
Puff/SparkPuff/Spark: single Channel unit
WaveWave: CICR
Global Global wavewave: concertedinteraction of cells
Skeletal muscle fibers and connective
tissues
ExcitationExcitation--ContractionContraction (EC) (EC) CouplingCoupling
(Anetseder and Roewer, Maligne Hyperthermie; Anästhesiologie, Springer Verlag, HD)
ExcitationExcitation NervNerv
Action potentialAction potential MuscleMuscle
depolarisationdepolarisation
CaCa2+2+ transienttransientRyRRyR
Tension Tension ActinActin
DevelopmentDevelopment MyosinMyosin
Voltage sensitive Ca2+ channels (Cav 1.1)Heteromultimers:
1 ion pore, gating function and drug binding site
2- , 2 highly glycosylated attached to -subunit via disulfide bonds; the domain modulates the kinetic properties
: localized intracellularly and is involved in the membrane trafficking of 1 subunits
: glycoprotein, having four transmembrane segments
Pharmakologisches Institut der Medizinischen Universität Wien
Adopted from : Melzer and Dietze, Acta Physiol. Scand. 171:367(2001)
SS
DHP - Receptor ( 15 )
TT - Membrane
I II III IV
Ryanodine receptor(RyR1)
N C
SR - Membrane
Ca2+
CaM
FKBP
2
1
ExcitationExcitation--ContractionContraction CouplingCouplingof Skeletal Muscleof Skeletal Muscle
Pharmakologisches Institut der Medizinischen Universität Wien
SS
DHP - Receptor ( 15 )
TT - Membrane
I II III IV
Ryanodine receptor(RyR1)
N C
SR - Membrane
Ca2+
FKBP
2
1
CaM
ExcitationExcitation--ContractionContraction CouplingCouplingof Skeletal Muscleof Skeletal Muscle
Adopted from : Melzer and Dietze, Acta Physiol. Scand. 171:367(2001)
Pharmakologisches Institut der Medizinischen Universität Wien
SS
DHP - Receptor ( 15 )
TT - Membrane
I II III IV
Ca2+
Ryanodine receptor(RyR1)
N C
SR - Membrane
Ca2+
FKBP
2
1
CaM
ExcitationExcitation--ContractionContraction CouplingCouplingof Skeletal Muscleof Skeletal Muscle
Adopted from : Melzer and Dietze, Acta Physiol. Scand. 171:367(2001)
Pharmakologisches Institut der Medizinischen Universität Wien
CaCa2+2+ Release Release channelchannel: : Ryanodine Ryanodine ReceptorReceptor
• Three isoforms; related to InsP3 receptor• RyR1(skeletal muscle) • RyR2 (cardiac) • RyR3 (brain, ubiquitous)
Pharmakologisches Institut der Medizinischen Universität Wien
Pharmakologisches Institut der Medizinischen Universität Wien, Hohenegger
Ryanodine receptor Type 1: skeletal muscle isoform
Type 2: cardiac isoform (also in brain and others)
Type 3: ubiquitous, with exceptions
Ryanodine, alkaloid from Ryania speciosa
NH2 COOH
TM 1-4
D1D3 D2
PP** CaMCaM
FKBP
Homotetramer: 560 kDa per subunit, 5037 aa
Ryanodine receptor Type 1
RyanodineInstitute of Pharmacology, Medical University Vienna, Hohenegger
EmergingEmerging mutationsmutations in RyR2 in RyR2
Associated with arrhythmia (catecholaminergic polymorphogenic ventricular tachycardia, suden heart death)
and heart failurePharmakologisches Institut der Medizinischen Universität Wien
RyRRyR11 and RyRand RyR22 mutationsmutations
Yano M et al. (2006)
Eindeutig zugewiesene Erkrankungen bei Eindeutig zugewiesene Erkrankungen bei
genetischen Defekten im genetischen Defekten im RyanodinrezeptorgenRyanodinrezeptorgen
RyR1- Mutationen: maligne Hyperthermie central core disease
RyR2- Mutationen:ARVC: arrhythmogenic right ventricular dysplasiaCPVT: Catecholaminergic polymorphic ventriculartachycardia
Pharmakologisches Institut der Medizinischen Universität Wien
Malignant Hyperthermia (MH)
• lifethreatening
• acute pharmacogenetic disorder
• developping during or after a generalanaesthesia
Other related diseasesCentral Core disease
Special RyR1 mutations:King-Denborough-Syndrom
RYR1 gene Arg2452Trp
NADH staining reduced =
less mitochondria
Fleckig/spotted = „core-like“
Muscular Dystrophieshigher risk vor malignant hyperthermia
Freeman Sheldon SyndromeMHC3 mutations: embryonic SKM myosin heavy chain 3 expressed
EtiologyEtiology and and PathogenesisPathogenesis of MH of MH withwithRyR1 RyR1 mutationsmutations
• autosomal-dominant inherited disorder, Chr.19q13.1
• incidence of the genetic MH predisposition is 1:10000
• clinical incidence about 1:30000; not every patient(mutation) developes a MH crisis
• specific early changes are the raise of the endexpiratoryCO2 together with the metabolic acidosis
• hyperthermia is a late sign.
• Rhabdomyolysis is a sign of the severity of the MH
Pathophysiology•Volatile anaesthetics (Chloroform, Ether, Halothane, Enflurane, Isoflurane, Sevoflurane, Deflurane)
• and/or suxamethonium, succinylxholine = 2 x Ach
• cause a raise in the myoplasmatic calcium concentration
• contractions lead to muscle injury and
• metabolic acidosis (when CO2 further raises then also respiratory acidosis)
• hyperkalemia, raised creatinkinase and myoglobinuria, arecaused by a damaged cell membrane
RhabdomyolyseRhabdomyolyse--MyoglobinurieMyoglobinurie
Necrosis
Differential Differential diagnosisdiagnosis
Thyreotoxicosis
Pheochromocytoma
Porphyria,
Histamine liberation (allergic reactions)
Hypovolemia
Hypoxia and hyperventilation
Epilepsia
Malignant neuroleptic syndrome
CaseCase reportreport
• Masseter spasm = chewing musculature
• Generalised skeletal muscle fasciculations
• Metabolic acidosis, later resiratory acidosis
• Raise of the creatin kinase and temperature
• Arrhythmias and tachycardia
TherapyTherapy I I
Masseterspasm or abortive MH crisis (mild form)
•Stop triggering (volatile anesthetics) and adminster 100% O2
•Deepen anesthesia with opioids, benzodiazepines (centralrelaxent), barbiturates or propofol
•Adjust ventilation according to blood gas analysis and endexpiratory CO2
•Check immediately, after 30 min, 4h, 12h, 24h blood gases, electrolytes, creatin kinase, myoglobin and lactat (arterialcatheter)
•Stop surgery, if fulminant MH crisis otherwise continue
•Give Dantrolene 2.5 mg/kg intravenous as bolus
TherapyTherapy IIIIFulminant MH crisis (severe form)
•Stop triggering, remove vaporizer and hyperventilation with100% O2
•Deepen anesthesia with opioids and sedatives, muscle relaxationwith a non depolarizing relaxant
•Check lab (see above), prepare dantrolene perfusion
•Dantrolene 2.5 mg/kg i.v. bolus, repeat bolus untilhypermetabolism stops (endexpiratory CO2), give dantrolen 10 mg/kg over 24 h continuously
•Sodium bicarbonate according to blood gas analysis or blind (1-2 mval/kg)
TherapyTherapy IIIIII
•Antiarrhythmic therapy with betablocker (esmolol 0.25 mg/kg i.v.) or lidocaine (1 mg/kg i.v.)
•Stop surgery as soon as possible
•Cooling: extremity or ice water through a nasogastric tube
•Postopersative Intensive care unit: monitoring: arterialcatheter, central venous catheter, swan-ganz-catheter, urinarycatheter; Force diuresis
•Check renal function, possible renal failure (myoglobin), coagulation, temperature, electrolytes and creatinkinase
ConsequencesConsequences
• Inform patient and relatives
• Test patient and relatives for MH susceptibility in a MH diagnostic center (in vitro contracture test, IVCT)
• If positive: MH susceptibility ID card
ConsequencesConsequences• Inform patient and relatives
• test patient and relatives for MH susceptibility in a MH diagnostic center (in vitro contracture test, IVCT)
• if positive: MH susceptibility ID card
In vitro In vitro contractioncontraction testtest
In vitro In vitro contractioncontraction testtest
MH
control
In vitro In vitro contractioncontraction testtestMH
control
TypicalTypical MH MH familyfamily
MH Abzeichen für Patientenmit positivem IVCT
ThisThis isis the ENDthe ENDbeautifulbeautiful friendfriend…………..