The role of integrins in the modulation of neurotransmitter release from motor nerve terminals by stretch and hypertonicity.
Integrins are found at most or all synapses and play a variety of roles. At frog neuromuscular junctions, mechanical tension on integrins due to muscle stretch or hypertonicity causes a powerful modulation of release efficacy. Understanding the mechanism(s) of integrin-mediated modulation will likely further our understanding of mechanisms of neurotransmitter release. The modulation of evoked release with stretch occurs with no detectable delay, does not adapt, and bypasses the Ca(2+) triggering step in vesicle fusion. It depends primarily on integrin bonds to native ligands and requires that one or more proteins in the link between integrins and vesicle fusion be dephosphorylated. Hypertonicity, studied in both frog and Drosophila terminals, causes a larger but slower phasic-tonic change in spontaneous release, which is also Ca(2+)-independent and mostly dependent on integrins, but not dependent on the phosphorylation state of molecules in its pathway of action. In Drosophila, the integrin-dependent component involves the cAMP/PKA pathway, and is absent in mutants lacking PKA. Both stretch and hypertonicity responses in frog terminals are enhanced by agents that elevate PKA levels, suggesting that, in frogs, the cAMP/PKA cascade primarily determines the size of the pool of vesicles available for release by the integrin-mediated mechanism and is not a direct intermediary in the modulation. Evoked release is affected little or even inhibited by hypertonicity. In Drosophila, the inhibition can be explained by a decrease in Ca(2+) influx. The effect of hypertonicity on evoked release in frogs may similarly be a balance between mechanisms that enhance spontaneous release and those that suppress I (Ca).
Grinnell
Alan D
AD
Department of Physiology, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1751, USA. adg@ucla.edu
Chen
Bo-Ming
BM
Kashani
Amir
A
Lin
Jennifer
J
Suzuki
Kazuhiro
K
Kidokoro
Yoshiaki
Y
D000818:Animals; D006801:Humans; D016023:Integrins / Q000502:physiology*; D009045:Motor Endplate / Q000378:metabolism / Q000502:physiology; D009046:Motor Neurons / Q000378:metabolism* / Q000502:physiology; D009119:Muscle Contraction / Q000502:physiology; D009470:Muscle Spindles / Q000378:metabolism* / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism* / Q000502:physiology; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000502:physiology
D016023:Integrins; D018377:Neurotransmitter Agents