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The Journal of Neuroscience, January 4, 2006, 26(1):311-318; doi:10.1523/JNEUROSCI.2920-05.2006

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Cellular/Molecular
Activation of Protein Kinase C in Sensory Neurons Accelerates Ca²⁺ Uptake into the Endoplasmic Reticulum

Yuriy M. Usachev,¹ Anthony J. Marsh,² Tanner M. Johanns,² Michelle M. Lemke,² and Stanley A. Thayer²

¹Department of Pharmacology, University of Iowa, Iowa City, Iowa 52242, and ²Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

The rate of Ca²⁺ clearance from the neuronal cytoplasm affects the amplitude, duration, and localization of Ca²⁺ signals and influences a variety of Ca²⁺-dependent functions. We reported previously that activation of protein kinase C (PKC) accelerates Ca²⁺ efflux in rat sensory neurons mediated by the plasma membrane Ca²⁺-ATPase isoform 4 (PMCA4). Here we show that sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA)-mediated Ca²⁺ uptake into intracellular stores is also accelerated by PKC activation. The rate of intracellular Ca²⁺ concentration ([Ca²⁺]_i) clearance was studied after small (<350 nM) action potential-induced Ca²⁺ loads in rat dorsal root ganglion neurons. Under these conditions, mitochondrial Ca²⁺ uptake and Na⁺/Ca²⁺ exchange do not significantly influence [Ca²⁺]_i recovery. Phorbol dibutyrate (PDBu) increased the rate of [Ca²⁺]_i clearance by 71% in a manner sensitive to the selective PKC inhibitors GF109203x (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide) and calphostin. PKC-dependent acceleration was still observed (39%) when the PKC-sensitive PMCA isoform was knocked down by expression of an antisense PMCA4 cDNA (AS4). Direct measurement of Ca²⁺ in the endoplasmic reticulum (ER) lumen revealed that PKC increased the rate of store refilling more than twofold after depletion by treatment with cyclopiazonic acid. ER refilling was less complete in PDBu-treated cells, although, in AS4-expressing cells, PDBu accelerated the rate without reducing the ER capacity, suggesting that PMCA and SERCA compete for Ca²⁺. Thus, activation of PKC accelerates the clearance of Ca²⁺ from the cytoplasm by the concerted stimulation of Ca²⁺ sequestration and Ca²⁺ efflux.

Key words: PKC; SERCA; PMCA; ER; Ca²⁺ uptake; Mag-indo-1; sensory neuron

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Received July 14, 2005; revised October 15, 2005; accepted November 10, 2005.

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