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The Journal of Neuroscience, March 16, 2005, 25(11):2853-2864; doi:10.1523/JNEUROSCI.4313-04.2005

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Cellular/Molecular
Signaling Microdomains Regulate Inositol 1,4,5-Trisphosphate-Mediated Intracellular Calcium Transients in Cultured Neurons

Simon N. Jacob,^1,3,5 Chi-Un Choe,^1,4,5 Per Uhlen,^1,5 Brenda DeGray,¹ Mark F. Yeckel,^2,5 and Barbara E. Ehrlich^1,5

Departments of ¹Pharmacology and Cellular and Molecular Physiology and ²Neurobiology, Yale University, New Haven, Connecticut 06520, ³Physiologisches Institut, University of Freiburg, D-79104 Freiburg, Germany, ⁴Institute for Neural Signal Transduction, Zentrum für Molekulare Neurobiologie Hamburg, University of Hamburg, D-20251 Hamburg, Germany, and ⁵Neurosciences Institute of the Marine Biological Laboratory, Woods Hole, Massachusetts 02543

Ca²⁺ signals in neurons use specific temporal and spatial patterns to encode unambiguous information about crucial cellular functions. To understand the molecular basis for initiation and propagation of inositol 1,4,5-trisphosphate (InsP₃)-mediated intracellular Ca²⁺ signals, we correlated the subcellular distribution of components of the InsP₃ pathway with measurements of agonist-induced intracellular Ca²⁺ transients in cultured rat hippocampal neurons and pheochromocytoma cells. We found specialized domains with high levels of phosphatidylinositol-4-phosphate kinase (PIPKI) and chromogranin B (CGB), proteins acting synergistically to increase InsP₃ receptor (InsP₃R) activity and sensitivity. In contrast, Ca²⁺ pumps in the plasma membrane (PMCA) and sarco-endoplasmic reticulum as well as buffers that antagonize the rise in intracellular Ca²⁺ were distributed uniformly. By pharmacologically blocking phosphatidylinositol-4-kinase and PIPKI or disrupting the CGB-InsP₃R interaction by transfecting an interfering polypeptide fragment, we produced major changes in the initiation site and kinetics of the Ca²⁺ signal. This study shows that a limited number of proteins can reassemble to form unique, spatially restricted signaling domains to generate distinctive signals in different regions of the same neuron. The finding that the subcellular location of initiation sites and protein microdomains was cell type specific will help to establish differences in spatiotemporal Ca²⁺ signaling in different types of neurons.

Key words: InsP₃; PIPKI; chromogranin; signaling microdomain; calcium imaging; hippocampal neurons

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Received Oct 17, 2004; revised January 28, 2005; accepted January 31, 2005.

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