Department of Physiology & Program in Neuroscience, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
J Cell Physiol. 2010 Oct;225(1):276-88. doi: 10.1002/jcp.22263.
Opioids modulate the electrical activity of magnocellular neurons (MCN) and inhibit neuropeptide release at their terminals in the neurohypophysis. We have previously shown that micro-opioid receptor (MOR) activation induces a stronger inhibition of oxytocin (OT) than vasopressin (AVP) release from isolated MCN terminals. This higher sensitivity of OT release is due, at least in part, to the selective targeting of R-type calcium channels. We now describe the underlying basis for AVP's weaker inhibition by MOR activation and provide a more complete explanation of the complicated effects on neuropeptide release. We found that N-type calcium channels in AVP terminals are differentially modulated by MOR; enhanced at lower concentrations but increasingly inhibited at higher concentrations of agonists. On the other hand, N-type calcium channels in OT terminals were always inhibited. The response pattern in co-labeled terminals was analogous to that observed in AVP-containing terminals. Changes in intracellular calcium concentration and neuropeptide release corroborated these results as they showed a similar pattern of enhancement and inhibition in AVP terminals contrasting with solely inhibitory responses in OT terminals to MOR agonists. We established that fast translocation of Ca(2+) channels to the plasma membrane was not mediating current increments and thus, changes in channel kinetic properties are most likely involved. Finally, we reveal a distinct Ca-channel beta-subunit expression between each type of nerve endings that could explain some of the differences in responses to MOR activation. These results help advance our understanding of the complex modulatory mechanisms utilized by MORs in regulating presynaptic neuropeptide release.
阿片类物质调节大细胞神经元（MCN）的电活动，并抑制神经垂体末端神经肽的释放。我们之前已经表明，μ型阿片受体（MOR）的激活诱导更强的抑制催产素（OT）释放比血管加压素（AVP）从分离的 MCN 末端。这种 OT 释放的更高敏感性至少部分归因于 R 型钙通道的选择性靶向。我们现在描述了 AVP 释放受 MOR 激活抑制较弱的基础，并提供了对神经肽释放的复杂影响的更完整解释。我们发现，AVP 末端的 N 型钙通道被 MOR 差异调节；在较低浓度下增强，但在较高浓度的激动剂下逐渐抑制。另一方面，OT 末端的 N 型钙通道始终被抑制。共标记末端的反应模式类似于在含 AVP 的末端观察到的模式。细胞内钙浓度和神经肽释放的变化证实了这些结果，因为它们在 AVP 末端显示出与 MOR 激动剂在 OT 末端的仅抑制反应相反的增强和抑制的相似模式。我们确定 Ca2+通道的快速易位到质膜不介导电流增加，因此，通道动力学特性的变化很可能参与其中。最后，我们揭示了每种神经末梢之间存在独特的 Ca 通道β亚基表达，这可以解释对 MOR 激活反应的一些差异。这些结果有助于我们深入了解 MOR 用于调节突触前神经肽释放的复杂调节机制。
