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The Journal of Neuroscience, September 10, 2003, 23(23):8423-8431
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Modulation of Synaptic Transmission by the BCL-2 Family Protein BCL-xL
Elizabeth A. Jonas,2,8
Daniel Hoit,2,8
John A. Hickman,3
Teresa A. Brandt,4
Brian M. Polster,4
Yihru Fannjiang,5
Erin McCarthy,6,8
Marlena K. Montanez,7,8
J. Marie Hardwick,4,5 and
Leonard K. Kaczmarek1,8
Departments of 1Pharmacology and 2Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06250, 3Institut de Recherches Servier, Suresnes 92150, Paris, France, Departments of 4Molecular Microbiology and Immunology and 5Pharmacology and Molecular Sciences, Johns Hopkins School of Public Health, Baltimore, Maryland 21205, 6Wake Forest University, Winston-Salem, North Carolina 27109, 7Mount Holyoke College, South Hadley, Massachusetts 01075, and 8Marine Biological Laboratory, Woods Hole, Massachusetts 02543
BCL-2 family proteins are known to regulate cell death during development by influencing the permeability of mitochondrial membranes. The anti-apoptotic BCL-2 family protein BCL-xL is highly expressed in the adult brain and localizes to mitochondria in the presynaptic terminal of the adult squid stellate ganglion. Application of recombinant BCL-xL through a patch pipette to mitochondria inside the giant presynaptic terminal triggered multiconductance channel activity in mitochondrial membranes. Furthermore, injection of full-length BCL-xL protein into the presynaptic terminal enhanced postsynaptic responses and enhanced the rate of recovery from synaptic depression, whereas a recombinant pro-apoptotic cleavage product of BCL-xL attenuated postsynaptic responses. The effect of BCL-xL on synaptic responses persisted in the presence of a blocker of mitochondrial calcium uptake and was mimicked by injection of ATP into the terminal. These studies indicate that the permeability of outer mitochondrial membranes influences synaptic transmission, and they raise the possibility that modulation of mitochondrial conductance by BCL-2 family proteins affects synaptic stability.
Key words: BCL-2; BCL-xL; squid; neurotransmitter release; mitochondria; ATP
Received April 7, 2003;
revised June 10, 2003;
accepted July 8, 2003.
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