Analgesic action of adenosine A1 receptor involves the dephosphorylation of glycine receptor α1ins subunit in spinal dorsal horn of mice
Analgesic action of adenosine A1 receptor involves the dephosphorylation of glycine receptor α1ins subunit in spinal dorsal horn of mice
复制标题
腺苷A1受体的镇痛作用涉及小鼠脊髓背角甘氨酸受体α1ins亚基的去磷酸化
DOI：
10.1016/j.neuropharm.2020.108219
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发表时间：
2020-10-01
影响因子：
4.7
通讯作者：
Hu, Xiao-Dong
中科院分区：
文献类型：
--
作者：
Diao, Xin-Tong;Yao, Lin;Hu, Xiao-Dong
甘氨酸受体α 1（ins）亚单位位于脊髓背角浅层的抑制性突触，参与甘氨酸能抑制伤害性神经元的兴奋和传递。细胞外信号调节激酶（ERK）在Ser 380处的α 1（ins）磷酸化已被证明可降低甘氨酸能突触电流，并有助于脊髓去抑制。我们发现，完全弗氏佐剂诱导的外周炎症增加了小鼠脊髓背角Ser 380的磷酸化，这种磷酸化被腺苷A1受体（A1 R）的特异性激活所抑制。蛋白磷酸酶-1（PP 1）是一种广泛分布的丝氨酸/苏氨酸磷酸酶，是MR降低Ser 380磷酸化所必需的。我们的数据表明，G β γ二聚体，当Gi蛋白偶联的MR激活后释放，与PP 1相互作用，并指导这种磷酸酶α 1（ins），允许Ser 380残基的完全去磷酸化。通过病毒表达β-肾上腺素能受体激酶（β ARKct）的C-末端尾部，G β-γ二聚体的螯合作用使PP 1与α 1（ins）复合物解离，导致Ser 380的强烈磷酸化。同时，G β-γ抑制损害了A1 R减轻炎性疼痛的能力。A1 R对Ser 380磷酸化的抑制作用也归因于CFA小鼠中ERK的失活。因此，我们的数据确定甘氨酸受体α 1（ins）亚单位作为一个重要的目标，腺苷能抑制炎症性疼痛。
Glycine receptor alpha 1(ins) subunit is located at inhibitory synapses in the superficial dorsal horn of adult spinal cord and is engaged in the glycinergic inhibition of nociceptive neuronal excitability and transmission. The alpha 1(ins) phosphorylation at Ser380 by extracellular signal-regulated kinase (ERK) has been shown to decrease glycinergic synaptic currents and contribute to spinal disinhibition. Here we found that peripheral inflammation induced by Complete Freund's Adjuvant increased Ser380 phosphorylation in spinal cord dorsal horn of mice, which was repressed by specific activation of adenosine A1 receptor (A1R). Protein phosphatase-1 (PP1), a ubiquitously-distributed serine/threonine phosphatase, was required for MR to reduce Ser380 phosphorylation. Our data showed that G beta gamma dimer, when released after activation of Gi protein-coupled MR, interacted with PP1 and directed this phosphatase to alpha 1(ins), allowing for the full dephosphorylation of Ser380 residue. Sequestration of G beta gamma dimer by viral expression of the C-terminal tail of beta-adrenergic receptor kinase (beta ARKct) dissociated PP1 from alpha 1(ins )complex, leading to robust Ser380 phosphorylation. Meanwhile, G beta gamma inhibition compromised the ability of A1R to alleviate inflammatory pain. The inhibitory effect of A1R on Ser380 phosphorylation was also attributed to the inactivation of ERK in CFA mice. Our data thus identified glycine receptor alpha 1(ins )subunit as an important target for adenosinergic suppression of inflammatory pain.