ACTIVATION OF G-PROTEINS BIDIRECTIONALLY AFFECTS APOPTOSIS OF CULTURED CEREBELLAR GRANULE NEURONS

Cultured cerebellar granule neurons maintained in depolarizing concent rations of K+ (25 mM) and then switched to physiological concentration s of K+ (5 mM) undergo apoptosis. We now report that activation of spe cific G proteins robustly and bidirectionally affects apoptosis of cul tured rat cerebellar granule neurons. Stimulation of G(s) with cholera toxin completely blocks apoptosis induced by nondepolarizing concentr ations of K+, whereas stimulation of G(0)/G(1) with the wasp venom pep tide mastoparan induces apoptosis of cerebellar granule neurons even i n high (depolarizing) concentrations of K+. Moreover, pretreatment of cerebellar granule neurons with cholera toxin attenuates neuronal deat h induced by mastoparan, By contrast, pertussis toxin, cell-permeable analogues of cyclic AMP, and activators of protein kinase A do not aff ect apoptosis of cultured cerebellar granule neurons, These data sugge st that G proteins may function as key switches for controlling the pr ogrammed death of mammalian neurons, especially in the developing CNS.