The critical role of lipid rafts nanodomains in the cross-talk between calcium and reactive oxygen and nitrogen species in cerebellar granule neurons apoptosis by extracellular potassium deprivation

Carlos Gutierrez-Merino; Dorinda Marques-da-Silva; Sofia Fortalezas; Alejandro K. Samhan-Arias; Carlos Gutierrez-Merino; Dorinda Marques-da-Silva; Sofia Fortalezas; Alejandro K. Samhan-Arias

doi:10.3934/molsci.2016.1.12

AIMS Molecular Science

2016, Volume 3, Issue 1: 12-29. doi: 10.3934/molsci.2016.1.12

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The critical role of lipid rafts nanodomains in the cross-talk between calcium and reactive oxygen and nitrogen species in cerebellar granule neurons apoptosis by extracellular potassium deprivation

Dept. Biochemistry and Molecular Biology, Faculty of Sciences, University of Extremadura, 06006-Badajoz, Spain

Received: 06 December 2015 Accepted: 17 January 2016 Published: 21 January 2016

The apoptosis of cerebellar granule neurons (CGN) induced by low-potassium in serum free medium in vitro has become a widely used model for neuronal apoptosis during in vivo brain development. In this review we shall summarize first the basic features of this model for neuronal apoptosis. Next, we shall focus on the L-type calcium channels (LTCC) inactivation as the primary pro-apoptotic signal in low K⁺-induced CGN death. This apoptotic process can be split into two major and sequential cellular signaling phases: one reversible phase that offers a temporal window for therapeutic interventions to prevent neuronal death, and an irreversible later phase. Therefore, we shall comment next the critical role of reactive oxygen species (ROS) production and major ROS sources triggering the entry of CGN in the irreversible stages of low K⁺-induced apoptosis. Then, we shall present the experimental evidences showing clustering of LTCC and ROS producing enzymes in plasma membrane lipid rafts of CGN matured in vitro, which have opened new perspectives for cell signaling in the early and reversible phase of this apoptosis. The role of lipid rafts nanodomains as fast response calcium/nitric oxide transducers of the switch of CGN to low K⁺ medium will be discussed next. The two major conclusions drawn from this review are: (1) deregulation of the pool of cytochrome b₅ reductase associated to plasma membrane-lipid rafts, at least in part due to overexpression of cytochrome b₅, can account for the critical superoxide anion overshot which triggers the entry in the irreversible phase of low K⁺ apoptosis of CGN, and (2) LTCC inactivation is rapidly transduced by lipid rafts nanodomains into a large drop of cytosolic calcium, a switch-off of nitric oxide production and subsequent inactivation of survival signaling pathways dependent on the activity of CaMKII, PKA and Akt/PKB kinases.
- apoptosis,
- cerebellar granule neurons,
- cytosolic calcium,
- reactive oxygen and nitrogen species,
- lipid rafts,
- L-type calcium channels,
- cytochrome b5 reductase,
- nNOS,
- CaMKII and other lipid rafts-associated protein kinases
Citation: Carlos Gutierrez-Merino, Dorinda Marques-da-Silva, Sofia Fortalezas, Alejandro K. Samhan-Arias. The critical role of lipid rafts nanodomains in the cross-talk between calcium and reactive oxygen and nitrogen species in cerebellar granule neurons apoptosis by extracellular potassium deprivation[J]. AIMS Molecular Science, 2016, 3(1): 12-29. doi: 10.3934/molsci.2016.1.12

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Abstract

The apoptosis of cerebellar granule neurons (CGN) induced by low-potassium in serum free medium in vitro has become a widely used model for neuronal apoptosis during in vivo brain development. In this review we shall summarize first the basic features of this model for neuronal apoptosis. Next, we shall focus on the L-type calcium channels (LTCC) inactivation as the primary pro-apoptotic signal in low K⁺-induced CGN death. This apoptotic process can be split into two major and sequential cellular signaling phases: one reversible phase that offers a temporal window for therapeutic interventions to prevent neuronal death, and an irreversible later phase. Therefore, we shall comment next the critical role of reactive oxygen species (ROS) production and major ROS sources triggering the entry of CGN in the irreversible stages of low K⁺-induced apoptosis. Then, we shall present the experimental evidences showing clustering of LTCC and ROS producing enzymes in plasma membrane lipid rafts of CGN matured in vitro, which have opened new perspectives for cell signaling in the early and reversible phase of this apoptosis. The role of lipid rafts nanodomains as fast response calcium/nitric oxide transducers of the switch of CGN to low K⁺ medium will be discussed next. The two major conclusions drawn from this review are: (1) deregulation of the pool of cytochrome b₅ reductase associated to plasma membrane-lipid rafts, at least in part due to overexpression of cytochrome b₅, can account for the critical superoxide anion overshot which triggers the entry in the irreversible phase of low K⁺ apoptosis of CGN, and (2) LTCC inactivation is rapidly transduced by lipid rafts nanodomains into a large drop of cytosolic calcium, a switch-off of nitric oxide production and subsequent inactivation of survival signaling pathways dependent on the activity of CaMKII, PKA and Akt/PKB kinases.

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