Abstract
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.
Highlights
Regulation of the size of a releasable pool of neurotransmitter and its probability of release contribute to both short-term and longterm changes in the strength of neurotransmission
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
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
Summary
Regulation of the size of a releasable pool of neurotransmitter and its probability of release contribute to both short-term and longterm changes in the strength of neurotransmission. Sustained elevations in presynaptic calcium during rapid, repetitive neuronal firing have been correlated with enhancement of synaptic transmission in a number of studies (Swandulla et al, 1991; Dittman and Regehr, 1998; Wang and Kaczmarek, 1998; Augustine, 2001; Sakaba and Neher, 2001). Repetitive firing produces a change in conductance on presynaptic mitochondrial membranes (Jonas et al, 1999). The conductance change requires extracellular calcium and occurs after a delay, suggesting that calcium entry through voltage-gated channels reaches mitochondria during high-frequency firing, when.
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