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[Ca 2+ ]ext (1000 m M)

REGULATION OF INTRACELLULAR CALCIUM. [Ca 2+ ]ext (1000 m M). Ca2+ATPase. Pi. [Ca 2+ ]cyt (0.1 m M). [Ca 2+ ]er (100 m moles). [Ca 2+ ]m ( 0.1 m M). [CaX] ( 100 m moles). H +. [Na + ]c. [K + ]ext. [H + ]. ATPase. ATPase. CaM. [K + ]ext. GLUCAGON a 2 -ADRENERGIC

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[Ca 2+ ]ext (1000 m M)

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  1. REGULATION OF INTRACELLULAR CALCIUM [Ca 2+]ext (1000mM) Ca2+ATPase Pi [Ca 2+]cyt (0.1mM) [Ca 2+]er (100mmoles) [Ca 2+]m ( 0.1mM) [CaX] ( 100mmoles) H+ [Na+]c [K+]ext [H+] ATPase ATPase CaM [K+]ext GLUCAGON a2-ADRENERGIC b-ADRENERGIC VASOPRESSIN [H+] [Na+]ext [Ca 2+]ext _

  2. MITOCHONDRIAL CALCIUM TRANSPORT CYTOSOL DILTIAZEM RUTHENIUM RED [Ca 2+]c [2H+]c [2Na+]c [Ca 2+]c ELECTRO- NEUTRAL ELECTROGENIC 0.5mM -180mV DpH 0.1mM Ca2+ [Ca 2+]m [2H+]m [Ca 2+]m [2Na+]m MATRIX  MATRIX CALCIUMPYRUVATE DEHYDROGENASE PHOSPHATASE (0.8-1mM) ISOCITRATE DEHYDROGENASE 2-OXOGLUTARATE DEHYDROGENASE PYRUVATE OXIDATION AND TCA CYCLE ACTIVITY PYROPHOSPHATASE ACTIVITY INCREASED PYROPHOSPHATE LEADS TO SWELLING, ACTIVATION OF RESPIRATORY CHAIN, INCREASED ADENINE NUCLEOTIDE CONTENT AND INCREASED ATP/ADP RATIO.

  3. O OH O P O 1,2-DIACYLGLYCEROL PHOSPHATIDYLINOSITOL RAPID BREAKDOWN FOLLWED BY RESYNTHESIS OH OH O- OH OH O OH PHOSPHATIDYLINOSITOL- 4 PHOSPHATE O P O 1,2-DIACYLGLYCEROL OH OH O- OH OPO32- O OPO32- O P O 1,2-DIACYLGLYCEROL PHOSPHATIDYLINOSITOL- 4,5 BISPHOSPHATE 1-2% OF TOTAL INOSITOL LIPIDS OH OH O- OH OPO32- SITE OF HYDROLYSIS HYDROLYSIS OF PHOSPHATIDYL INOSITOL 4,5 BISPHOSPHATE

  4. RECEPTOR-STIMULATED BREAKDOWN OF PHOSPHATIDYL INOSITOL 4,5 BISPHOSPHATE PtdINS 4,5P2 (RAPID DEPLETION) PtdINS 4,P (RAPID DEPLETION) STIMULUS Ca2+ INDEPENDENT GTP Ins 1,4,5 P3 (RAPID ACCUMULATION) 1,2 DIACYLGLYCEROL (RAPID ACCUMULATION) 32P-ATP Ins 1,4 P2 (ACCUMULATION) PHOSPHATIDATES (ACCUMULATES, STIMULATED 32P LABELLING) Ins 1 P (ACCUMULATION) PHOSPHATIDYL-CMP INHIBITED BY Li+ Ptd INOSITOL (DEPLETED, STIMULATED 32P LABELLING) INOSITOL (SLOW ACCUMULATION)

  5. PHOSPHOLIPASE Cb ACTIVATION Ca2+ H PHOSPHATIDYL INOSITOL 4,5- BISPHOSPHATE 1,2-DIACYL GLYCEROL PHOSPHO-LIPASE Cb Active g aq OH PIP2 Ca2+ PKC ACTIVE b IP3 IP3-DEPENDENT Ca2+ CHANNEL P P P P P P GTP ARACHIDONIC ACID Ca2+ E + Cal2 + 4Ca2+ ECal2(Ca2+)4 Ca2+ ENDOPLASMIC RETICULUM PHYSIOLOGICAL RESPONSE

  6. PHOSPHOLIPASE Cb 4 ISOENZYMES b1, b2, b3 AND b4 – ALL REQUIRE Ca2+ HAVE DIFFERENT TISSUE DISTRIBUTION EF HAND Y X PH C2 H2N COOH PH DOMAIN – BINDS MEMBRANE INOSITOL LIPIDS – PtdIns(3)P, ALSO ACTS AS SITE OF INTERACTION WITH bg SUBUNITS EF HAND – NORMALLY Ca2+ BINDING DOMAINS BUT UNCLEAR X AND Y DOMAINS – FORM THE CATALYTIC CORE C2 DOMAIN – INTERACTS WITH a-SUBUNITS OF Gq. Gaq ACTIVATES ALL ISOENZYMES b1 AND b3 >b2 Gbg ACTIVATES ALL ISOENZYMES EXCEPT b4. b2 >b1 AND b3

  7. BREAKDOWN OF PIP2 BY PHOSPHOLIPASE Cb EXTRA CELLULAR PIP2 IP3 + DAG SS tm1 tm4 tm2 tm3 OH H2N OH OH PIP2 IP3 + DAG bg bg aq aq GTP Y X C2 PH INTRA CELLULAR PI3P PI3P GDP Y X C2 PH GTP

  8. CALCIUM RELEASE BY INSOSITOL PHOSPHATES RELEASE OF CALCIUM REQUIRES THE 4,5 PHOSPHATE GROUPS IN THE MOLECULE Ins1,4P2 IS INEFFECTIVE Ins4,5P2 IS WEAK Ins2,4,5P3 IS EFFECTIVE BUT LESS SO THAN Ins1,4,5P3 HORMONAL STIMULATION RESULTS IN THE PRODUICTION OF TWO INOSITOL TRIS PHOSPHATES Ins1,4,5 P3 AND Ins1,3,4 P3

  9. R1 R1 OH R2 R2* OH OPO32- 2-O3PO 2-O3PO OH OH OH OH OH OH OPO32- OPO32- OH OPO32- 2-O3PO 2-O3PO OH OH OPO32- OPO32- OH OH OPO32- OPO32- METABOLISM OF PHOSPHATIDYL INOSITOL 4,5 BISPHOSPHATE OPO32- O DIACYLGLYCEROL O P O OH *ARACHIDONIC ACID OH O- OH OPO32- PI 4,5P2 PHOSPHOLIPASE C PHOSPHATASE Ins (1,4,5)P3 Ins (1,4,)P2 Ca2+-DEPENDENT KINASE PHOSPHATASE Ins (1,3,4)P3 Ins (1,3,4,5)P4

  10. IP3 RECEPTOR Ca 2+ CaMKINASE II TETRAMER (3 ISOFORMS) IP3 cAMPPK + BINDING DOMAIN IP3 NH2 + IP3 IP3 Ca2+ ATP ATP IP3 + P COUPLING DOMAIN P PKC IP3 CALMODULIN (TYPES I&II) DAG COOH PIP2 TRANS- MEMBRANE DOMAIN PLC

  11. CONTROL OF Ca2+ RELEASE BY Ca2+ Ca2+   Ca2+ Ca2+ + + CALMODULIN PERIPHERAL TISSUES Ca2+ CALMEDIN CEREBELLUM Ca2+ Ca2+ Ca2+ _ _ _ SUBMAXIMAL IP3

  12. TRP FAMILY OF PROTEINS (Ca2+ CHANNEL) CIF (IP4?) RYANODINE RECEPTORS CONTROL OF CALCIUM ENTRY INTO CELLS

  13. CALCIUM TRAVELS IN WAVES THROUGHOUT THE CELL  Ca2+ IS PROPAGATED BY A SERIES OF WAVES THROUGHOUT THE CELL FROM A SINGLE LOCUS – Ca2+ INDUCED Ca2+ RELEASE  Ca2+ OCCURS AS S SERIES OF REPETITIVE SPIKES, THE FREQUENCY AND AMPLITUDE OF WHICH ARE AGONIST AND CONCENTRATION DEPENDENT.

  14. FEEDBACK REGULATION BY RGS PROTEIN SS _ _ _ + + DAG PIP2 + + + RGS PKC PLCb _ _ INACTIVE ACTIVE RGS Ca2+/CaM RGS HAS GTPase ACTIVATING ACTIVITY WHEN ACTIVATED BY Ca2+/CALMODULIN. TURNS OFF PLCb IP3 IP3R ER PIP3 Ca2+ Gabg REGULATOR OF G PROTEIN SIGNALLING

  15. INTERACTION OF CALMODULIN WITH CALCIUM Ca2+/CaM bound To CaM KII Peptide Ca2+/CaM APO CaM

  16. CALMODULIN DEPENDENT KINASE II AUTO- INHIBITORY SUBUNIT ASSOCIATION H2N COOH CaM CATALYTIC AUTOINHIBITORY DOMAIN OCCUPIES AND BLOCKS CATALYTIC SITE. Ca2+/CALMODULIN REMOVES AUTOINHIBITORY DOMAIN FROM CATALYTIC SITE RESULTING IN AUTOPHOSPHORYLATION AND ACTIVATION. CONSTITUTIVELY ACTIVE IN THE ABSENCE OF Ca2+/CALMODULIN, Km FOR ATP 145mM, DECREASED TO 10-20mM. NH2 10-12 SUBUNITS CALMODULIN DEPENDENT KINASE IV SIMILAR TO ABOVE BUT MONOMERIC, STRONG SEQUENCE HOMOLOGY

  17. CRYSTAL STRUCTURE OF CaM KI ATP BINDING DOMAIN AUTOINHIBITORY DOMAIN AND Ca2+/CaM BINDING DOMAIN

  18. CALPAIN CLEAVAGE CATALYTIC DOMAIN REGULATORY DOMAIN V1 C1 V2 C2 V3 C3 V4 C4 V5 HYDROPHILIC HYDROPHOBIC H2N COO- PSEUDO- SUBSTRATE PHORBOL BINDING CALCIUM BINDING ATP BINDING SUBSTRATE TT TT ST S ZINC FINGERS S C1 C1 C4 C4 TRANSIENT ACTIVATION PS DAG PHORBOL ESTERS ATP STAUROSPORINE C3 C2 C3 C2 Ca2+ CALPAIN CLEAVAGE DOWN REGULATION

  19. STRUCTURE OF PKC ISOFORMS ACTIVATED BY Ca2+, DIACYLGLYCEROL, PHOSPHATIDYL SERINE, FREE FATTY ACIDS ACTIVATED BY DIACYLGLYCEROL, PHOSPHATIDYL SERINE, FREE FATTY ACIDS NOT ACTIVATED BY DIACYLGLYCEROL/ PHORBOL ESTERS PHOSPHATIDYL INOSITOL (3,4,5) TRIPHOSPHATE (PI-3-KINASE)

  20. REGULATION OF PROTEIN PHOSPHATASE AND PHOSPHODIESTERASE BY CALCIUM TYPE 1 Ca2+ /CALMODULIN-DEPENDENT PHODPHODIESTERASE MONOMER 58-75 kDa. N-TERMINAL CALMODULIN BINDING DOMAIN. SEVERAL FORMS SHOWING DIFFERENT ACTIVITIES TOWARDS cGMP AND cAMP. REVERSIBLY ACTIVATED BY CALMODULIN IN THE PRESENCE OF Ca2+ (Ca2+ )4 (Km , Vmax). PDE2 + CAL2 +4Ca2+ PDE2.CAL2 PHOSPHORYLATED BYcAMPPK CAUSING DECREASED AFFINITY OF CALMODULIN FOR ENZYME AND ACTIVATION BY Ca2+/CALMODULIN TYPE 2B PROTEIN PHOSPHATASE (PP-2B) CONSISTS OF A SUBUNIT (CATALYTIC) AND B SUBUNIT (CALCIUM BINDING). DEPHOSPHORYLATES INHIBITOR-1 AND REGULATORY SUBUNIT OF PKA, a-SUBUNIT OF PHOSPHORYLASE KINASE AND MYOSIN LIGHT CHAIN KINASE. BINDS TO CALMODULIN TO INCREASE ACTIVITY 10-FOLD. INCREASES Vmax. LITTLE ACTIVITY TOWARDS METABOLIC ENZYMES

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