Reciprocal modulation of phospholipase Cβ isoforms:: Adaptation to chronic morphine
Reciprocal modulation of phospholipase Cβ isoforms:: Adaptation to chronic morphine
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DOI：
10.1073/pnas.2335885100
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发表时间：
2003-11-11
影响因子：
11.1
通讯作者：
Gintzler, AR
中科院分区：
文献类型：
--
作者：
Chakrabarti, S;Liu, NJ;Gintzler, AR
磷脂酰肌醇周转和钙动员是急性和慢性阿片类药物作用的基本决定因素。磷脂酰肌醇特异性磷脂酶C（PLC）是关键的信号传导酶，其在介导阿片调节三磷酸肌醇产生和细胞溶质钙分布（许多急性和慢性阿片效应的底物）中起关键作用。值得注意的是，磷酸化的13种异构体的PLC，由激酶上调后，慢性吗啡，是一个有效的方式为他们的监管。直接评估豚鼠纵肌肌间神经丛组织中的PLC β 1和PLC β 3磷酸化，发现阿片类药物耐受诱导后发生了实质性变化。值得注意的是，这种调节的方向是亚型特异性的。PLC β 1的磷酸化显著降低，而PLC β 3的磷酸化显著增强，变化不伴随PLC β 1或PLC β 3蛋白质含量的改变。与慢性吗啡相反，阿片类药物初始纵向肌肉肌间神经丛组织的急性吗啡治疗减弱了PLC β 3磷酸化，这一作用也通过内源性阿片类药物表现出来，其通过急性纳洛酮显著增加PLC β 3磷酸化的能力反映出来。这表明PLC β磷酸化是动态调节的。PLC β 1和PLC β 3活性受磷酸化负调节。因此，它们伴随的相互磷酸化将改变这些亚型对PLC/Ca 2+信号传导的相对贡献，这是鉴于它们的差异调节特征的显著转变。信号传导酶的相同亚类内的两种同种型的磷酸化（活性）的相互调节，具有高度结构相似性并具有相同生物学功能的蛋白质，代表了迄今为止尚未认识到的对慢性吗啡的适应方式。
Phosphoinositide turnover and calcium mobilization are fundamental determinants of acute and chronic opioid effects. Phosphoinositide-specific phospholipase C (PLC) are key signaling enzymes that play a pivotal role in mediating opioid modulation of inositol trisphosphate production and cytosolic calcium distribution, substrates for many acute and chronic opioid effects. Notably, phosphorylation of the 13 isoforms of PLC, by kinases that are up-regulated after chronic morphine, is a potent modality for their regulation. Direct assessment of PLCbeta1 and PLCbeta3 phosphorylation in the guinea pig longitudinal muscle myenteric plexus tissue revealed substantial alterations after the induction of opioid tolerance. Notably, the direction of this modulation is isoform-specific. Phosphorylation of PLCbeta1 is significantly reduced, whereas that of PLCbeta3 is substantially augmented, changes not accompanied by altered content of PLCbeta1 or PLCbeta3 protein. In contrast to chronic morphine, acute morphine treatment of opioid naive longitudinal muscle myenteric plexus tissue attenuates PLCbeta3 phosphorylation, an effect also manifested by endogenous opioids that is reflected by the ability of acute naloxone to substantially augment PLCbeta3 phosphorylation. This indicates that PLCbeta phosphorylation is dynamically regulated. PLCbeta1 and PLCbeta3 activities are negatively modulated by phosphorylation. Thus, their concomitant reciprocal phosphorylation would alter the relative contribution of these isoforms to PLC/Ca2+ signaling, a significant shift in light of their differential regulatory characteristics. Reciprocal modulation of the phosphorylation (activity) of two isoforms within the same subclass of signaling enzyme, proteins that have a high degree of structural similarity and subserve the same biological function, represents an adaptation modality to chronic morphine that has heretofore not been recognized.