NMDA受体的氧敏感性：与NR2亚基组成及新生神经元缺氧耐受性的关系

Oxygen sensitivity of NMDA receptors: relationship to NR2 subunit composition and hypoxia tolerance of neonatal neurons.

作者信息

Bickler P E, Fahlman C S, Taylor D M

机构信息

Department of Anesthesia, Sciences 257, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0542, USA.

出版信息

Neuroscience. 2003;118(1):25-35. doi: 10.1016/s0306-4522(02)00763-7.

DOI:10.1016/s0306-4522(02)00763-7

PMID:12676134

Abstract

Neonatal rats survive and avoid brain injury during periods of anoxia 25 times longer than adults. We hypothesized that oxygen activates and hypoxia suppresses NMDA receptor (NMDAR) responses in neonatal rat neurons, explaining the innate hypoxia tolerance of these cells. In CA1 neurons isolated from neonatal rat hippocampus (mean postnatal age [P] 5.8 days), hypoxia (PO(2) 10 mm Hg) reduced NMDA receptor-channel open-time percentage and NMDA-induced increase in Ca(2+) (NMDA DeltaCa(2+)) by 38 and 68% (P<0.01), respectively. In P20 neurons the reductions were not significant. In P3-10 CA1 neurons within intact hippocampal slices, hypoxia reduced NMDA DeltaCa(2+) by 52% (P=0.002) and decreased NMDA-induced death by 45% (P=0.004). Phalloidin, a microtubule stabilizer, prevented hypoxia-induced inhibition of NMDA DeltaCa(2+) in P3-10 neurons. To test whether NMDARs prevalent in neonates (NR1 plus NR2B or NR2D subunits) are inhibited by hypoxia compared with those in mature neurons (NR2A and NR2C), we expressed these receptors in Xenopus oocytes. Compared with responses in 21% O(2), hypoxia (PO(2) 17 mm Hg) reduced currents from neonatal type NR1/NR2D receptors by 25%, increased currents from NR1/NR2C by 18%, and had no effect on NR1/NR2A or NR1/NR2B. Modulation of NMDARs by hypoxia may play an important role in the hypoxia tolerance of the mammalian neonate. In addition, oxygen sensing by NMDARs could play a significant role in postnatal brain development.

摘要

新生大鼠在缺氧期间的存活时间及避免脑损伤的时间比成年大鼠长25倍。我们推测，氧气激活而缺氧抑制新生大鼠神经元中的NMDA受体（NMDAR）反应，这解释了这些细胞天生的缺氧耐受性。在从新生大鼠海马体分离的CA1神经元（出生后平均年龄[P]5.8天）中，缺氧（PO₂ 10 mmHg）使NMDA受体通道开放时间百分比和NMDA诱导的[Ca²⁺]i增加（NMDA ΔCa²⁺）分别降低了38%和68%（P<0.01）。在出生后20天的神经元中，这种降低并不显著。在完整海马体切片内出生后3 - 10天的CA1神经元中，缺氧使NMDA ΔCa²⁺降低了52%（P = 0.002），并使NMDA诱导的细胞死亡减少了45%（P = 0.004）。鬼笔环肽，一种微管稳定剂，可防止出生后3 - 10天神经元中缺氧诱导的对NMDA ΔCa²⁺的抑制。为了测试与成熟神经元（NR2A和NR2C）中的NMDAR相比，新生神经元中普遍存在的NMDAR（NR1加上NR2B或NR2D亚基）是否受到缺氧抑制，我们在非洲爪蟾卵母细胞中表达了这些受体。与在21% O₂中的反应相比，缺氧（PO₂ 17 mmHg）使新生型NR1/NR2D受体的电流降低了25%，使NR1/NR2C的电流增加了18%，而对NR1/NR2A或NR1/NR2B没有影响。缺氧对NMDAR的调节可能在哺乳动物新生儿的缺氧耐受性中起重要作用。此外，NMDAR的氧感应可能在出生后脑发育中起重要作用。