Han P, Lucero M T
Interdepartmental Neuroscience Program, University of Utah, Salt Lake City, UT 84108, USA.
Neuroscience. 2005;134(3):745-56. doi: 10.1016/j.neuroscience.2005.05.007.
Pituitary adenylate cyclase activating polypeptide has been shown to reduce apoptosis in neonatal cerebellar and olfactory receptor neurons, however the underlying mechanisms have not been elucidated. In addition, the neuroprotective effects of pituitary adenylate cyclase activating polypeptide have not been examined in adult tissues. To study the effects of pituitary adenylate cyclase activating polypeptide on neurons in apoptosis, we measured caspase activation in adult olfactory receptor neurons in vitro. Interestingly, we found that the protective effects of pituitary adenylate cyclase activating polypeptide were related to the absence of a 4-aminopyridine (IC50=144 microM) sensitive rapidly inactivating potassium current often referred to as A-type current. In the presence of 40 nM pituitary adenylate cyclase activating polypeptide 38, both A-type current and activated caspases were significantly reduced. A-type current reduction by pituitary adenylate cyclase activating polypeptide was blocked by inhibiting the phospholipase C pathway, but not the adenylyl cyclase pathway. Our observation that 5 mM 4-aminopyridine mimicked the caspase inhibiting effects of pituitary adenylate cyclase activating polypeptide indicates that A-type current is involved in apoptosis. This work contributes to our growing understanding that potassium currents are involved with the activation of caspases to affect the balance between cell life and death.
垂体腺苷酸环化酶激活多肽已被证明可减少新生小脑和嗅觉受体神经元的凋亡，但其潜在机制尚未阐明。此外，垂体腺苷酸环化酶激活多肽在成体组织中的神经保护作用尚未得到研究。为了研究垂体腺苷酸环化酶激活多肽对凋亡神经元的影响，我们在体外测量了成体嗅觉受体神经元中的半胱天冬酶激活情况。有趣的是，我们发现垂体腺苷酸环化酶激活多肽的保护作用与一种通常称为A型电流的对4-氨基吡啶（IC50 = 144 microM）敏感的快速失活钾电流的缺失有关。在存在40 nM垂体腺苷酸环化酶激活多肽38的情况下，A型电流和活化的半胱天冬酶均显著减少。垂体腺苷酸环化酶激活多肽对A型电流的减少可通过抑制磷脂酶C途径而非腺苷酸环化酶途径来阻断。我们观察到5 mM 4-氨基吡啶模拟了垂体腺苷酸环化酶激活多肽的半胱天冬酶抑制作用，这表明A型电流参与了凋亡过程。这项工作有助于我们进一步理解钾电流与半胱天冬酶激活有关，从而影响细胞生死平衡。
