Bcl-xL Inhibitor ABT-737 Reveals a Dual Role for Bcl-xL in Synaptic Transmission

Abstract

A role for BCL-xL in regulating neuronal activity is suggested by its dramatic effects on synaptic function and mitochondrial channel activity. When recombinant BCL-xL is injected into the giant presynaptic terminal of squid stellate ganglion or applied directly to mitochondrial outer membranes within the living terminal, it potentiates synaptic transmission acutely, and it produces mitochondrial channel activity. The squid, however, is a genetically intractable model, making it difficult to apply genetic tools in squid to explore the role of endogenous BCL-xL in synaptic function. Therefore the small molecule inhibitor ABT-737, a mimetic of the BH3-only protein BAD, binding to the BH3-binding domain pocket, was tested in squid, revealing a dual role for BCL-xL. ABT-737 slowed recovery of synaptic responses after repetitive synaptic activity, indicating that endogenous BCL-xL is necessary for timely recovery of rapidly firing synapses. Unexpectedly, however, ABT-737 also protected neurons from hypoxia-induced synaptic rundown and from increased permeability of the mitochondrial outer membrane during hypoxia. This implies that endogenous BCL-xL or a modified form of BCL-xL, such as the N-truncated, proteolytic, pro-apoptotic cleavage product, ΔN BCL-xL, contributes to injurious responses of the hypoxic synapse. To determine if ABT-737 is also an inhibitor of ΔN BCL-xL, recombinant ΔN BCL-xL protein was injected into the synapse. ABT-737 potently inhibited synaptic rundown induced by recombinant ΔN BCL-xL. These observations support the possibility that endogenous proteolysis or a functionally equivalent modification of BCLxL is responsible for the deleterious effects of hypoxia on synaptic activity.

Phase I study of obatoclax mesylate (GX15-070), a small molecule pan–Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia

“…The neurologic toxicity was expected based on preclinical toxicology experiments and was decreased by prolonging the rate of infusion. A recent report implicates Bcl-xl in synaptic function with disruption induced in vitro by the Bcl-2/Bclxl/Bcl-w antagonist ABT-737, 13 thus supporting the conclusion that the CNS effects of obatoclax, which is known to cross the blood brain barrier, represent an on-target effect. Monitoring of peripheral blood counts throughout the study revealed occasional episodes of grade 3 or 4 neutropenia and thrombocytopenia.…”

BAD: undertaker by night, candyman by day

“…Remarkably, the protective effect of ischemic preconditioning in this experimental paradigm occurs despite caspase-3 activation (Miyawaki et al, 2008). Emerging studies suggest that, beyond apoptosis, regulated interaction of BAD and BAD-like ligands and BCL-X L in neurons may further influence cellular bioenergetics and determine the ATP levels available for synapse formation or recovery after ischemic insult (Hickman et al, 2008). Specifically, the interaction of BAD and BCL-X L may affect the refilling of synaptic vesicles and trafficking of mitochondria to synaptic termini for efficient neurotransmission (Jonas et al, 2003;Li et al, 2008).…”

Long-term depression: a cell biological view

“…Although further studies are needed, it appears that apoptotic mechanisms can also regulate axonal morphology. It will be interesting to investigate whether local activation of caspases can locally affect synapse structure and function from the presynaptic side [98,99].…”