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The Journal of Neuroscience, May 12, 2004, 24(19):4698-4708; doi:10.1523/JNEUROSCI.5523-03.2004

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Cellular/Molecular
Ca²⁺-Binding Protein-1 Facilitates and Forms a Postsynaptic Complex with Ca_v1.2 (L-Type) Ca²⁺ Channels

Hong Zhou,^1 * Seong-Ah Kim,^1 * Elizabeth A. Kirk,¹ Alyssa L. Tippens,¹ Hong Sun,¹ Françoise Haeseleer,² and Amy Lee¹

¹Department of Pharmacology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322, and ²Department of Opthalmology, University of Washington School of Medicine, Seattle, Washington 98195

Ca²⁺-binding protein-1 (CaBP1) is a Ca²⁺-binding protein that is closely related to calmodulin (CaM) and localized in somatodendritic regions of principal neurons throughout the brain, but how CaBP1 participates in postsynaptic Ca²⁺ signaling is not known. Here, we describe a novel role for CaBP1 in the regulation of Ca²⁺ influx through Ca_v1.2 (L-type) Ca²⁺ channels. CaBP1 interacts directly with the ₁ subunit of Ca_v1.2 at sites that also bind CaM. CaBP1 binding to one of these sites, the IQ domain, is Ca²⁺ dependent and competitive with CaM binding. The physiological significance of this interaction is supported by the association of Ca_v1.2 and CaBP1 in postsynaptic density fractions purified from rat brain. Moreover, in double-label immunofluorescence experiments, CaBP1 and Ca_v1.2 colocalize in numerous cell bodies and dendrites of neurons, particularly in pyramidal cells in the CA3 region of the hippocampus and in the dorsal cortex. In electrophysiological recordings of cells transfected with Ca_v1.2, CaBP1 greatly prolonged Ca²⁺ currents, prevented Ca²⁺-dependent inactivation, and caused Ca²⁺-dependent facilitation of currents evoked by step depolarizations and repetitive stimuli. These effects contrast with those of CaM, which promoted strong Ca²⁺-dependent inactivation of Ca_v1.2 with these same voltage protocols. Our findings reveal how Ca²⁺-binding proteins, such as CaM and CaBP1, differentially adjust Ca²⁺ influx through Ca_v1.2 channels, which may specify diverse modes of Ca²⁺ signaling in neurons.

Key words: calcium; calmodulin; channel; postsynaptic; facilitation; inactivation

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Received Dec 16, 2003; revised April 12, 2004; accepted April 15, 2004.

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