The main objective of the experiments described in this application is to develop and evaluate a highly innovative, mechanistically rational neuroprotective strategy in cerebral ischemia. During the last ten years with support from this grant, we have characterized a Zn2+-mediated apoptotic-enabling signaling pathway that culminates with the SNARE-dependent insertion of p38/Src dual phosphorylated Kv2.1-encoded K+ channels in the neuronal plasma membrane. This process results in a dramatic enhancement of delayed-rectifier K+ currents, mediating the loss of intracellular K+ required for the establishment of a permissive, optimal environment for caspase and nuclease activation in injured neurons. Although interfering with the processes responsible for the apoptotic K+ current surge can effectively block neuronal cell death, none of the upstream signaling events leading to the K+ current enhancement are specific for this pathway. In preliminary studies presented here, we show that channels lacking a SNARE binding domain do not support an apoptotic current surge. Moreover, we show that overexpression of the SNARE-binding intracellular channel domain alone is neuroprotective in vitro. We hypothesize that interfering with a cellular process that trigger the Kv2.1-mediated apoptotic K+ current surge may provides a highly specific and effective therapeutic strategy for neuroprotection in stroke and related injury. In order to adequately evaluate this hypothesis we will address the following experimental Specific Aims: First, we will characterize in detail the phosphorylation and SNARE-dependent mechanisms leading to Kv2.1-mediated apoptotic K+ current surges~ and second, we will investigate whether interfering with the SNARE/Kv2.1 interaction using cell-penetrating peptides is a viable neuroprotective strategy in a rodent stroke model. The long-term goal of our research program is to devise novel neuroprotective approaches for the treatment of stroke and related neurodegenerative conditions. The loss of intracellular K+ via a surge of Kv2.1-mediated K+ currents may constitute a ubiquitous requirement for apoptotic cell death of cortical and hippocampal neurons. As effective neuroprotective strategies to treat human neurological conditions continue to be highly elusive, conceptually innovative studies, such as targeting neuronal apoptotic K+ currents, are not only of potentially high significance, but also urgently needed.

Public Health Relevance

The research proposed in this application will help us understand the role of potassium channel function in neuronal cell death. Most importantly, research conducted during this project may reveal novel avenues for developing a new class of neuroprotective drugs to prevent brain damage during stroke and related conditions.

National Institute of Health (NIH)
Research Project (R01)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bosetti, Francesca
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Shah, Niyathi H; Schulien, Anthony J; Clemens, Katerina et al. (2014) Cyclin e1 regulates Kv2.1 channel phosphorylation and localization in neuronal ischemia. J Neurosci 34:4326-31
Shah, Niyathi Hegde; Aizenman, Elias (2014) Voltage-gated potassium channels at the crossroads of neuronal function, ischemic tolerance, and neurodegeneration. Transl Stroke Res 5:38-58
McCord, Meghan C; Aizenman, Elias (2014) The role of intracellular zinc release in aging, oxidative stress, and Alzheimer's disease. Front Aging Neurosci 6:77
Perez-Rosello, Tamara; Anderson, Charles T; Schopfer, Francisco J et al. (2013) Synaptic Zn2+ inhibits neurotransmitter release by promoting endocannabinoid synthesis. J Neurosci 33:9259-72
Chorin, Ehud; Vinograd, Ofir; Fleidervish, Ilya et al. (2011) Upregulation of KCC2 activity by zinc-mediated neurotransmission via the mZnR/GPR39 receptor. J Neurosci 31:12916-26
Aras, Mandar A; Aizenman, Elias (2011) Redox regulation of intracellular zinc: molecular signaling in the life and death of neurons. Antioxid Redox Signal 15:2249-63
Hershfinkel, Michal; Aizenman, Elias; Andrews, Glen et al. (2010) Zinc bells rang in Jerusalem! Sci Signal 3:mr2
Hershfinkel, Michal; Kandler, Karl; Knoch, Megan E et al. (2009) Intracellular zinc inhibits KCC2 transporter activity. Nat Neurosci 12:725-7
Aras, Mandar A; Hara, Hirokazu; Hartnett, Karen A et al. (2009) Protein kinase C regulation of neuronal zinc signaling mediates survival during preconditioning. J Neurochem 110:106-17
Aras, Mandar A; Saadi, Robert A; Aizenman, Elias (2009) Zn2+ regulates Kv2.1 voltage-dependent gating and localization following ischemia. Eur J Neurosci 30:2250-7

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