[Ca2+]i modulation of cAMP-stimulated ciliary beat frequency via PDE1 in airway ciliary cells of mice
[Ca2+]i modulation of cAMP-stimulated ciliary beat frequency via PDE1 in airway ciliary cells of mice
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DOI：
10.1113/ep086681
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发表时间：
2018-03-01
影响因子：
2.7
通讯作者：
Nakahari, Takashi
中科院分区：
文献类型：
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作者：
Kogiso, Haruka;Hosogi, Shigekuni;Nakahari, Takashi
[Ca2+](i)在调节气道纤毛搏动频率（CBF）和纤毛弯曲角（CBA）中起着至关重要的作用。此外，Ca2+依赖性PDE1A存在于调节CBF的纤毛代谢中，通过调节cAMP的积累来改变CBF。该研究表明，CBF受到[Ca2+]的直接和间接作用的调节(i)；直接作用改变通过[Ca2+]介导的CBF (i)，间接作用改变通过cAMP介导的CBF， cAMP的积累受PDE1活性控制。当[Ca2+](i)降低到不同水平时，直接作用降低CBF，间接作用增加CBF。最终CBF由cAMP积累的程度决定，cAMP积累的程度由PDE1活性的抑制量决定，这取决于[Ca2+]的减少(i)；名义上无Ca2+溶液引起的轻微减少（没有通过PDE1积累cAMP）会降低CBF，而50m BAPTA-AM引起的极端减少通过抑制PDE1以类似于PDE1抑制剂（8MmIBMX）的方式通过cAMP积累增加CBF。[Ca2+](i)减少时CBA的增加小于CBF的增加，因为在CBA调节代谢中不存在PDE1A。相反，离子霉素（ionomycin）诱导的[Ca2+](i)的增加，通过PDE1A激活减少cAMP的积累，导致procaterol刺激的CBF增加比Ca2+无溶液减少的要慢。[Ca2+]的减少(i)刺激cAMP的积累，而[Ca2+]的增加(i)抑制cAMP在气道纤毛细胞中的积累。因此，[Ca2+]的变化(i)通过控制PDE1的活性，通过cAMP积累来调节CBF和CBA。
[Ca2+](i) plays crucial roles in the regulation of ciliary beat frequency (CBF) and ciliary bend angle (CBA) of airway cilia. Moreover, Ca2+-dependent PDE1A existing in the CBF-regulating metabolon of cilia modifies the CBF by regulating the cAMP accumulation. This study demonstrated that the CBF is regulated by a direct and an indirect action of [Ca2+](i); the direct action changes CBF mediated via [Ca2+](i), and the indirect action changes CBF mediated via cAMP, the accumulation of which is controlled by PDE1 activity. Upon reducing [Ca2+](i) to various levels, the direct action decreases CBF and the indirect action increases CBF. The final CBF is determined by the extent of cAMP accumulation, which is determined by the amount of inhibition of PDE1 activity, dependent on a reduction in [Ca2+](i); a slight decrease induced by a nominally Ca2+-free solution (no cAMP accumulation via PDE1) decreases CBF, and an extreme decrease induced by 50m BAPTA-AM increases CBF via cAMP accumulation by inhibiting PDE1 in a similar manner to a PDE1 inhibitor (8MmIBMX). The increase in CBA in response to a reduction in [Ca2+](i) is smaller than the increase in CBF, because no PDE1A exists in the CBA-regulating metabolon. On the contrary, an increase in [Ca2+](i) induced by ionomycin, which decreases cAMP accumulation by PDE1A activation, caused a slower procaterol-stimulated increase in CBF than that decreased by a Ca2+-free solution. A decrease in [Ca2+](i) stimulates cAMP accumulation, whereas an increase in [Ca2+](i) inhibits cAMP accumulation in airway ciliary cells. Thus, changes in [Ca2+](i) modulate CBF and CBA via cAMP accumulation by controlling the activity of PDE1.