[Frontiers in Bioscience 7, d1255-1279, May 1, 2002]


Stanley A. Thayer, Yuriy M. Usachev and William J. Pottorf, II

Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street, SE, Minneapolis, MN 55455-0217


1. Abstract
2. Introduction
3. Mitochondria
3.1. Mitochondria damp the amplitude and prolong the duration of [Ca2+]i increases
3.2. Modulation of mitochondrial uptake, storage and release of Ca2+
3.3. Modulating mitochondrial Ca2+ buffering alters neuronal function
4. Endoplasmic Reticulum (ER)
4.1. ER Ca2+ buffering and release - a capacity-dependent switch
4.2. Modulation of sarcoplasmic or endoplasmic reticulum Ca2+ ATPase (SERCA)
4.3. Modulation of ER Ca2+ storage capacity
4.4. Functional consequences of switching between Ca2+ release and uptake
5. Ca2+ Binding Proteins
6. Plasma Membrane Ca2+ ATPase (PMCA)
6.1. Alternative splicing generates Ca2+ pump isoforms with unique properties
6.2. PMCAs provide high affinity Ca2+ extrusion
6.3. Pharmacologic modulation of PMCAs
6.4. Selective modulation of PMCA isoforms by endogenous signaling pathways
6.5. PMCAs are sites where signaling pathways converge
7. Plasmalemmal Na+/ Ca2+ Exchange
7.1. Na+/ Ca2+ exchange provides low affinity, high turnover Ca2+ extrusion
7.2. Thermodynamic modulation of Na+/ Ca2+ exchange
7.3. Modulation of Na+/ Ca2+ exchange by second messengers
7.4. Pharmacologic modulation of Na+/ Ca2+ exchange
7.5. Functional consequences of modulating Na+/ Ca2+ exchange in neurons
8. Perspectives
8.1. Competing for Ca2+ - the integrated response
8.2. Future directions
9. Acknowledgements
10. References


Neurons are exquisitely sensitive to the duration, amplitude and localization of transient increases in intracellular Ca2+ concentration ([Ca2+]i). Modulation of Ca2+ uptake into the mitochondrion and endoplasmic reticulum, and efflux via the plasma membrane Ca2+ pump and Na+/Ca2+ exchange profoundly affect the shape of [Ca2+]i signals. Ca2+ clearance mechanisms are modulated by other signaling pathways, are sensitive to metabolic state and have a memory of the recent history of cell activation. We present here examples of pharmacologic and endogenous regulation of Ca2+ sequestration and efflux in neurons. Ca2+ clearance mechanisms differentially shape [Ca2+]i signals based on their affinity, capacity and location; their modulation alters specific neuronal functions. The increasingly apparent diversity of the molecular entities that make up the [Ca2+]i regulatory system reveals new sites or modulation. Specialized Ca2+ clearance mechanisms participate in unique cellular functions and thus, are important targets for pharmacological and physiological regulation of the neuron.