K(Ca)2 channels activation prevents [Ca(2+)](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 ([Ca(2+)](i)) are established hallmarks of neuronal cell death in acute and chronic neurological diseases. Here we show that pathological [Ca(2+)](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 [Ca(2+)](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.