1. Calcium  Cellular Signalling
Chapter 11
Calcium  Cellular Signalling
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FIGURE 11.1 The basic concepts of Ca2+ homeostasis. (From Carafoli, Copyright 2004, with permission from Elsevier.)
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FIGURE 11.2 Formation of puncta structure and redistribution of STIM1. Ca2+ store depletion leads to a rapid translocation of STIM1 into puncta and puncta-formed STIM1 migrates from ER sites to the plasma membrane. Thereafter, the CRAC activation domain (CAD) of STIM1 directly binds to the N- and C-termini of Orai1 to open the SOC (CRAC) channel. (From Kurosaki & Baba, Copyright 2010, with permission from Elsevier.)
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FIGURE 11.3 (A) The cytoplasmic Ca2+ is maintained at low levels in resting cells. Cytoplasmic [Ca2+] is maintained at ~100 nM by extrusion via plasma membrane Ca2+ ATPase (PMCA) and smooth endoplasmic reticular Ca2+ ATPase (SERCA) transporters. The Na/Ca exchanger (NCX), a major secondary regulator of [Ca2+], is electrogenic, exchanging three Na ions for one Ca2+. Intracellular Ca2+ hyperpolarises many cells by activating K+ channels, and in some cells, Cl channels. This decreases CaV channel activity but increases the driving force across active Ca2+-permeant channels. (B) In excitatory Ca2+ signalling, plasma membrane ion channels are triggered to open by changes in voltage, or extra- or intracellular ligand binding. When open, ~ 1 million Ca2+ ions/s/channel flow down the 20,000-fold [Ca2+]i gradient (ECa ~ +150 mV), maintained by elements shown in (A). Initial increases in [Ca2+] trigger more release, primarily from ER via Ca2+-sensitive ryanodine receptors (RyR). G-protein-coupled receptor (GPCR) or receptor tyrosine kinase-mediated activation of PLC cleaves PIP2 into inositol-(1,4,5)-trisphosphate (IP3) and diacylglycerol (DAG). IP3 is a ligand for the intracellular IP3R channel spanning the membrane of the ER. GPCRs catalyse the exchange of guanosine diphosphate (GDP) for GTP on G subunits, releasing active G and G subunits that in turn activate PLCb. RTKs dimerise upon ligand binding, autophosphorylate, and interact with other signalling proteins to activate PLC. (From Clapham, Copyright 2007, with permission from Elsevier.)
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FIGURE 11.4 Architecture of Ca2+-ATPase and its ion pumping mechanism. (a) A ribbon representation of Ca2+-ATPase in the E12Ca2+ state, viewed parallel to the membrane plane. Colours change gradually from the amino terminus (blue) to the carboxy terminus (red). Purple spheres (numbered and circled) represent bound Ca2+. Three cytoplasmic domains (A, N, and P), the -helices in the A-domain (A1A3), and those in the transmembrane domain (M1M10) are indicated. M1’ is an amphipathic part of the M1 helix lying on the bilayer surface. Docked ATP is shown in transparent space fill. Several key residues  E183 (A), F487 and R560 (N, ATP binding), D351 (phosphorylation site), D627 and D703 (P)  are shown in ball-and-stick. Axis of rotation (or tilt) of the A-domain is indicated with a thin orange line. PDB accession code is 1SU4 (E12Ca2+). (b) A cartoon illustrating the structural changes of the Ca2+-ATPase during the reaction cycle, based on the crystal structures in 7 different states. (From Toyoshima, Copyright 2009, with permission from Elsevier.)
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FIGURE 11.5 The reaction cycle of Ca2+-ATPase pumps. In the E1 conformation of the pump, Ca2+ is bound with high affinity at the cytoplasmic side of the plasmamembrane. In the E2 configuration, the binding site exposes Ca2+ to the external site of the plasma membrane, where its lower affinity for Ca2+ favours its release. (Adapted from Di Leva et al., Copyright 2008, with permission from Elsevier.)
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FIGURE 11.6 A schematic representation of the transport of Ca2+ in and out of mitochondria. The cartoon shows all the Ca2+ transporters, and stresses the activation of matrix dehydrogenases. The permeability transition pore (PTP) is enclosed in a dashed box because its role in Ca2+ release is not established. Abbreviations: AcetylCoA, acetyl-coenzyme A;  KGDH, -ketoglutarate dehydrogenase; NAD-IDH, NAD+-dependent isocitrate dehydrogenase; PDH, pyruvate dehydrogenase; TCA cycle, tricarboxylic acid cycle. (From Carafoli, Copyright 2003, with permission from Elsevier.)
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FIGURE 11.7 The microdomain concept of mitochondrial Ca2+ transport. Ca2+ penetrating from outside or released from the ER generates restricted domains of high Ca2+ concentration (20 M or more), adequate to activate the low-affinity Ca2+ uptake system of neighboring mitochondria. The Ca2+-releasing agonist shown is InsP3; however, other agonists acting on different channels (e.g., cADPr) also generate the Ca2þ hotspots. (From Carafoli, Copyright, 2002, National Academy of Sciences, USA.)
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FIGURE 11.8 The phosphoinsitide cascade.
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FIGURE 11.9 Decoding of the Ca2+ signal by conformational changes in EF hand proteins (CaM). CaM interacts with a 26-residue binding domain (red peptide, top right) of a skeletal muscle myosin light chain kinase termed M13. CaM (left) has bound Ca2+ (yellow shares) to its four EF hands. It has already undergone the change that has made its surface more hydrophobic, but it still is in the fully extended conformation. The interaction with M13 collapses it to a hairpin shape that engulfs the binding peptide. (From Carafoli, Copyright (2002) National Academy of Sciences, USA.)
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FIGURE The Ca2+-binding site of calmodulin.
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