Neuron-specific Bcl-2 homology 3 domain-only splice variant of Bak is anti-apoptotic in neurons, but pro-apoptotic in non-neuronal cells

We have identified and characterized N-Bak, a neuron-specific isoform of th e pro-apoptotic Bcl-2 family member Bak. N-Bak is generated by neuron-speci fic splicing of a novel 20-base pair exon, which changes the previously des cribed Bak, containing Bcl-2 homology (BH) domains BH1, BH2, and BH3, into a shorter BH3-only protein. ks demonstrated by reverse transcription-polyme rase chain reaction and RNase protection assay, N-Bak transcripts are expre ssed only in central and peripheral neurons, but not in other cells, wherea s the previously described Bak is expressed ubiquitously, but not in neuron s. Neonatal sympathetic neurons microinjected with N-Bak resisted apoptotic death caused by nerve growth factor (NGF) removal, whereas microinjected B ak accelerated NGF deprivation-induced death. Overexpressed Bak killed symp athetic neurons in the presence of NGF, whereas N-Bak did not. N-Bak was, h owever, still death-promoting when overexpressed in non-neuronal cells. Thu s, N-Bak is an anti-apoptotic BH3-only protein, but only in the appropriate cellular environment. This is the first example of a neuron-specific Bcl-2 family member.