Grinnell Alan D, Chen Bo-Ming, Kashani Amir, Lin Jennifer, Suzuki Kazuhiro, Kidokoro Yoshiaki
Department of Physiology, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095-1751, USA.
J Neurocytol. 2003 Jun-Sep;32(5-8):489-503. doi: 10.1023/B:NEUR.0000020606.58265.b5.
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).
整合素存在于大多数或所有突触中，并发挥多种作用。在青蛙神经肌肉接头处，由于肌肉拉伸或高渗作用于整合素的机械张力会对释放效率产生强大的调节作用。了解整合素介导的调节机制可能会进一步加深我们对神经递质释放机制的理解。拉伸引起的诱发释放调节没有可检测到的延迟，不适应，并且绕过了囊泡融合中的Ca(2+)触发步骤。它主要取决于整合素与天然配体的结合，并且要求整合素与囊泡融合之间联系中的一种或多种蛋白质去磷酸化。在青蛙和果蝇终末中研究的高渗作用会导致自发释放出现更大但更缓慢的时相-紧张性变化，这也是Ca(2+)非依赖性的，并且主要依赖于整合素，但不依赖于其作用途径中分子的磷酸化状态。在果蝇中，整合素依赖性成分涉及cAMP/PKA途径，并且在缺乏PKA的突变体中不存在。青蛙终末中的拉伸和高渗反应都被提高PKA水平的试剂增强，这表明在青蛙中，cAMP/PKA级联反应主要决定了通过整合素介导机制可用于释放的囊泡池的大小，并且不是调节中的直接中介。诱发释放受高渗作用影响很小甚至受到抑制。在果蝇中，这种抑制可以通过Ca(2+)内流减少来解释。高渗作用对青蛙诱发释放的影响可能同样是增强自发释放的机制与抑制I(Ca)的机制之间的平衡。
