Actions of BAX on mitochondrial channel activity and on synaptic transmission.
Changes in mitochondrial architecture and permeability facilitate programmed cell death. The BCL-2 family protein BAX is implicated in the formation of large "death channels" in outer mitochondrial membranes. We found that BAX-induced channels on mitochondria may have alternative functions. By patch clamping mitochondrial membranes inside the presynaptic terminal of the living squid giant synapse, we made direct measurements of channel activity produced by BAX application. Only infrequently did BAX application result in large conductance channels similar to those produced by a proapoptotic BCL-xL fragment or by application of a BH3-only peptide. Instead, the majority of outer mitochondrial channels induced by BAX had much smaller conductances than those found previously for the proapoptotic protein. Injection of BAX into the presynaptic terminal did not abolish synaptic transmission, contrary to previous findings with the proapoptotic fragment of BCL-xL. Instead, injection of BAX caused an increase in neurotransmitter release, as has also been found for the full-length antiapoptotic BCL-xL protein. We suggest that BAX can act to enhance synaptic efficacy in a normal physiological setting. Furthermore, the occasional large openings may reflect the function of "activated" BAX either to facilitate cell death or to play a physiological role in decreasing synaptic activity.
Jonas
Elizabeth A
EA
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. elizabeth.jonas@yale.edu
Hardwick
J Marie
JM
Kaczmarek
Leonard K
LK
D000818:Animals; D017209:Apoptosis; D002462:Cell Membrane / Q000378:metabolism; D004594:Electrophysiology; D007425:Intracellular Membranes / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D049834:Loligo; D008928:Mitochondria / Q000378:metabolism*; D005810:Multigene Family; D018377:Neurotransmitter Agents / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000737:chemistry; D017729:Presynaptic Terminals / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism / Q000502:physiology*; D051020:bcl-X Protein / Q000378:metabolism
D008081:Liposomes; D018377:Neurotransmitter Agents; D010455:Peptides; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein