Estevez Miguel, Estevez Annette O, Cowie Robin H, Gardner Kathy L
Veterans Administration Hospital Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
J Neurochem. 2004 Jan;88(1):102-13. doi: 10.1046/j.1471-4159.2003.02140.x.
Migraine is an episodic pain disorder whose pathophysiology is related to deficiency of serotonin signaling and abnormal function of the P/Q-type calcium channel, CACNA1A. Because the relationship of the CACNA1A channel to serotonin signaling is unknown and potentially of therapeutic interest we have used genetic analysis of the Caenorhabditis elegans ortholog of this calcium channel, UNC-2, to help identify candidate downstream effectors of the human channel. By genetic dissection of the lethargic mutant phenotype of unc-2, we have established an epistasis pathway showing that UNC-2 function antagonizes a transforming growth factor (TGF)-beta pathway influencing movement rate. This same UNC-2/TGF-beta pathway is required for accumulation of normal serotonin levels and stress-induced modulation of tryptophan hydroxylase (tph) expression in the serotonergic chemosensory ADF neurons, but not the NSM neurons. We also show that transgenic expression of the migraine-associated Ca2+ channel, CACNA1A, in unc-2 animals can functionally substitute for UNC-2 in stress-activated regulation of tph expression. The demonstration that these evolutionarily related channels share a conserved ability to modulate tph expression through their effects on TGF-beta signaling provides the first specific example of how CACNA1A function may influence levels of the critical migraine neurotransmitter serotonin.
偏头痛是一种发作性疼痛障碍，其病理生理学与血清素信号传导缺陷及P/Q型钙通道CACNA1A的功能异常有关。由于CACNA1A通道与血清素信号传导的关系尚不清楚，且可能具有治疗意义，我们利用对该钙通道秀丽隐杆线虫直系同源物UNC-2进行基因分析，以帮助确定人类通道的候选下游效应器。通过对unc-2嗜睡突变体表型的基因剖析，我们建立了一个上位性途径，表明UNC-2功能拮抗影响运动速度的转化生长因子（TGF）-β途径。正常血清素水平的积累以及血清素能化学感受ADF神经元而非NSM神经元中应激诱导的色氨酸羟化酶（tph）表达调节，都需要相同的UNC-2/TGF-β途径。我们还表明，在unc-2动物中转基因表达偏头痛相关的Ca2+通道CACNA1A，在应激激活的tph表达调节中可以在功能上替代UNC-2。这些进化相关通道通过对TGF-β信号传导的影响共享调节tph表达的保守能力，这一证明为CACNA1A功能可能影响关键偏头痛神经递质血清素水平提供了第一个具体例子。
