1. Calcium Signalling

2. Why Calcium? [Ca 2+ ] i maintained very low – Prevents precipitation of organic anions

3. Why Calcium? Divalency - stronger protein binding than monovalent ions. Large [Ca 2+ ] gradient [10 -7 vs. 10 -3 M]

4. PM Ca 2+ -ATPase ER Ca 2+ -ATPase – Calsequestrin Mitochondrial high capacity (low affinity) pump

5. Target TissueSignaling MoleculeMajor Responses LiverVasopressinGlycogen breakdown PancreasAChAmylase secretion Smooth muscleAChContraction Mast cellsAntigenHistamine secretion Blood plateletsThrombinaggregation

8. Turn the Pathway Off Voltage-gated Ca 2+ channels inactivate IP 3 rapidly dephosphorylated Ca 2+ rapidly pumped out Phosphatases are activated (CaMKII)

9. Ca 2+ as a 2 nd Messenger (cont’d) Ryanodine Receptors (RyR) Important for skeletal muscle Caffeine is an example of a reversible activator of RyRs IP3 receptors Inositol-1,4,5-P3

10. Gq Signalling - Calcium Signalling Tyrosine kinase Signalling – Calcium Signalling

14. Paari Dominic Swaminathan et al. Circulation Research. 2012;110:1661-1677 Copyright © American Heart Association, Inc. All rights reserved.

15. The domain structure of a calmodulin-dependent protein kinase II (CaMKII) monomer. Paari Dominic Swaminathan et al. Circulation Research. 2012;110:1661-1677 Copyright © American Heart Association, Inc. All rights reserved.

16. Ca-Responsive Transcriptional Activation cAMP-response element (CRE) CaM KII and Ras-ERK1/2 signaling pathways NFAT