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Protein Kinase C  Mediates Ethanol-Induced Up-regulation of L-Type Calcium Channels

Protein Kinase C  Mediates Ethanol-Induced Up-regulation of L-Type Calcium Channels. Journal of Biological Chemistry Vol. 273 No. 26 pp 16409 – 16414 1998. Background. Chronic alcohol exposure produces tolerance to the effects of alcohol BAC above 100 mM leads to coma in non-alcoholic

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Protein Kinase C  Mediates Ethanol-Induced Up-regulation of L-Type Calcium Channels

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  1. Protein Kinase C Mediates Ethanol-Induced Up-regulation of L-Type Calcium Channels Journal of Biological Chemistry Vol. 273 No. 26 pp 16409 – 16414 1998

  2. Background • Chronic alcohol exposure produces tolerance to the effects of alcohol • BAC above 100 mM leads to coma in non-alcoholic • Alcoholics can seem normal or only slightly intoxicated at BAC of 100 – 150 mM BAC  blood alcohol content

  3. Background • Voltage-dependent calcium channels are membrane proteins that open to allow influx of calcium ions when a neuron depolarizes • There are several types of VDCC, distinguished by their response to depolarization level, location, and sensitivity to various compounds: • L type: focus of this article, found in neurons • T type • N type • R • P/Q

  4. Background • Acute exposure of neuronal cell cultures to ethanol inhibits calcium influx through L-type channels • Chronic exposure leads to tolerance – a recovery of the “normal” calcium influx • Due to increased number of L-type calcium channels on cell surface

  5. Background • Protein kinase C is a serine/threonine kinase involved in many signaling pathways related to: • Cell growth & differentiation • Neurotransmitter release • Receptor regulation • Ion channel modulation • Gene expression

  6. Background • Many different types of PKC exist (a, bi, b2, g, d, e, z, l, m) • Chronic exposure to ethanol increases expression of PKCd and PKCe. • Compounds that inhibit activity of all PKCs can prevent the effect of ethanol on L-type calcium channels • Thus, the effect of ethanol on calcium channels may be mediated through its effect on PKC

  7. The Question • Which isozyme of PKC mediates the ethanol-induced up-regulation of L-type calcium channels?

  8. The Tools • PC12 cells transfected to express a peptide inhibitor of either PKCd or PKCe • These are called Vd and Ve, and exist in multiple versions (Vd1, Vd2, Ve1, Ve2, etc.) • Experimental strategies include exposing cells chronically to ethanol at various concentrations and measuring calcium uptake

  9. The Data

  10. The Vd fragment inhibits calcium uptake while the Ve does not

  11. The Vd fragment inhibits L-type calcium channel up-regulation while the Ve does not

  12. The Conclusions • Chronically exposing PC12 cells to ethanol: • activates PKCd and PKCe • Restores the “normal” calcium influx seen in the absence of ethanol • Increases the number of cell-surface L-type channels • Blocking the activity of PKCd but not PKCeprevents the effect of ethanol

  13. The Conclusions (continued) • These results identify PKCd as a regulator of L-type calcium channel density and a mediator of cellular adaptation to ethanol. • Since L-type calcium channels modulate drinking behavior and contribute to withdrawal, PKCd may play a key role in controlling alcohol dependence and consumption

  14. Next Step • Can inhibitors of PKCd reduce or prevent ethanol consumption and the development of alcohol dependence in animals?

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