Department of Oral Physiology and Institute of Oral Bioscience, School of Dentistry, Chonbuk National University, Jeonju, 561-756, Korea.
Endocrinology. 2011 Apr;152(4):1551-61. doi: 10.1210/en.2010-1191. Epub 2011 Feb 1.
It is well established that the GABA(A) receptor plays an important role in regulating the electrical excitability of GnRH neurons. Two different modes of GABA(A) receptor signaling exist: one mediated by synaptic receptors generating fast (phasic) postsynaptic currents and the other mediated by extrasynaptic receptors generating a persistent (tonic) current. Using GABA(A) receptor antagonists picrotoxin, bicuculline methiodide, and gabazine, which differentiate between phasic and tonic signaling, we found that ∼50% of GnRH neurons exhibit an approximately 15-pA tonic GABA(A) receptor current in the acute brain slice preparation. The blockade of either neuronal (NO711) or glial (SNAP-5114) GABA transporter activity within the brain slice revealed the presence of tonic GABA signaling in ∼90% of GnRH neurons. The GABA(A) receptor δ subunit is only found in extrasynaptic GABA(A) receptors. Using single-cell RT-PCR, GABA(A) receptor δ subunit mRNA was identified in GnRH neurons and the δ subunit-specific agonist 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol was found to activate inward currents in GnRH neurons. Perforated-patch clamp studies showed that 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol exerted the same depolarizing or hyperpolarizing effects as GABA on juvenile and adult GnRH neurons and that tonic GABA(A) receptor signaling regulates resting membrane potential. Together, these studies reveal the presence of a tonic GABA(A) receptor current in GnRH neurons that controls their excitability. The level of tonic current is dependent, in part, on neuronal and glial GABA transporter activity and mediated by extrasynaptic δ subunit-containing GABA(A) receptors.
已经证实，GABA(A) 受体在调节 GnRH 神经元的电兴奋性方面起着重要作用。GABA(A) 受体信号传递有两种不同模式：一种是通过产生快速（瞬态）突触后电流的突触受体介导，另一种是通过产生持续（紧张）电流的 extrasynaptic 受体介导。使用 GABA(A) 受体拮抗剂 picrotoxin、bicuculline methiodide 和 gabazine，它们可以区分瞬态和紧张信号，我们发现约 50%的 GnRH 神经元在急性脑切片制备中表现出约 15pA 的紧张性 GABA(A) 受体电流。在脑切片中阻断神经元 (NO711) 或神经胶质 (SNAP-5114) GABA 转运体的活性，揭示了约 90%的 GnRH 神经元存在紧张性 GABA 信号传递。GABA(A) 受体 δ 亚基仅存在于 extrasynaptic GABA(A) 受体中。使用单细胞 RT-PCR，鉴定出 GnRH 神经元中存在 GABA(A) 受体 δ 亚基 mRNA，并且 δ 亚基特异性激动剂 4,5,6,7-四氢异恶唑并[5,4-c]吡啶-3-醇被发现可激活 GnRH 神经元的内向电流。穿孔膜片钳研究表明，4,5,6,7-四氢异恶唑并[5,4-c]吡啶-3-醇对未成年和成年 GnRH 神经元的作用与 GABA 相同，具有去极化或超极化作用，紧张性 GABA(A) 受体信号传递调节静息膜电位。总之，这些研究揭示了 GnRH 神经元中存在紧张性 GABA(A) 受体电流，该电流控制其兴奋性。紧张电流的水平部分取决于神经元和神经胶质 GABA 转运体的活性，并由 extrasynaptic δ 亚基包含的 GABA(A) 受体介导。
