KCa2 channels activation prevents [Ca2+]i deregulation and reduces neuronal death following glutamate toxicity and cerebral ischemia

Exacerbated activation of glutamate receptor-coupled calcium channels and subsequent increase in intracellular calcium ([Ca2+](i)) are established hallmarks of neuronal cell death in acute and chronic neurological diseases. Here we show that pathological [Ca2+](i) deregulation occurring after glutamate receptor stimulation is effectively modulated by small conductance calcium-activated potassium (K(Ca)2) channels. We found that neuronal excitotoxicity was associated with a rapid downregulation of K(Ca)2.2 channels within 3 h after the onset of glutamate exposure. Activation of K(Ca)2 channels preserved K(Ca)2 expression and significantly reduced pathological increases in [Ca2+](i) providing robust neuroprotection in vitro and in vivo. These data suggest a critical role for K(Ca)2 channels in excitotoxic neuronal cell death and propose their activation as potential therapeutic strategy for the treatment of acute and chronic neurodegenerative disorders. Cell Death and Disease (2011) 2, e147; doi: 10.1038/cddis.2011.30; published online 21 April 2011