Seifi Mohsen, Brown James F, Mills Jeremy, Bhandari Pradeep, Belelli Delia, Lambert Jeremy J, Rudolph Uwe, Swinny Jerome D
Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, PO1 2DT, United Kingdom.
Institute for Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, University of Portsmouth, PO1 2DT, United Kingdom, Department of Gastroenterology, Queen Alexandra Hospital, Portsmouth, PO6 3LY, United Kingdom.
J Neurosci. 2014 Jul 30;34(31):10361-78. doi: 10.1523/JNEUROSCI.0441-14.2014.
The enteric nervous system (ENS) provides the intrinsic neural control of the gastrointestinal tract (GIT) and regulates virtually all GI functions. Altered neuronal activity within the ENS underlies various GI disorders with stress being a key contributing factor. Thus, elucidating the expression and function of the neurotransmitter systems, which determine neuronal excitability within the ENS, such as the GABA-GABAA receptor (GABAAR) system, could reveal novel therapeutic targets for such GI disorders. Molecular and functionally diverse GABAARs modulate rapid GABAergic-mediated regulation of neuronal excitability throughout the nervous system. However, the cellular and subcellular GABAAR subunit expression patterns within neurochemically defined cellular circuits of the mouse ENS, together with the functional contribution of GABAAR subtypes to GI contractility remains to be determined. Immunohistochemical analyses revealed that immunoreactivity for the GABAAR gamma (γ) 2 and alphas (α) 1, 2, 3 subunits was located on somatodendritic surfaces of neurochemically distinct myenteric plexus neurons, while being on axonal compartments of submucosal plexus neurons. In contrast, immunoreactivity for the α4-5 subunits was only detected in myenteric plexus neurons. Furthermore, α-γ2 subunit immunoreactivity was located on non-neuronal interstitial cells of Cajal. In organ bath studies, GABAAR subtype-specific ligands had contrasting effects on the force and frequency of spontaneous colonic longitudinal smooth muscle contractions. Finally, enhancement of γ2-GABAAR function with alprazolam reversed the stress-induced increase in the force of spontaneous colonic contractions. The study demonstrates the molecular and functional diversity of the GABAAR system within the mouse colon providing a framework for developing GABAAR-based therapeutics in GI disorders.
肠神经系统（ENS）为胃肠道（GIT）提供内在神经控制，并调节几乎所有的胃肠功能。ENS内神经元活动的改变是各种胃肠疾病的基础，压力是一个关键的促成因素。因此，阐明神经递质系统的表达和功能，这些系统决定了ENS内神经元的兴奋性，如γ-氨基丁酸-GABAA受体（GABAAR）系统，可能会揭示此类胃肠疾病的新治疗靶点。分子和功能多样的GABAARs调节整个神经系统中快速的GABA能介导的神经元兴奋性调节。然而，小鼠ENS神经化学定义的细胞回路内细胞和亚细胞GABAAR亚基表达模式，以及GABAAR亚型对胃肠收缩性的功能贡献仍有待确定。免疫组织化学分析显示，GABAARγ2和α1、2、3亚基的免疫反应性位于神经化学上不同的肌间神经丛神经元的树突体表面，而位于黏膜下神经丛神经元的轴突区。相比之下，α4-5亚基的免疫反应性仅在肌间神经丛神经元中检测到。此外，α-γ2亚基免疫反应性位于非神经元的Cajal间质细胞上。在器官浴研究中，GABAAR亚型特异性配体对结肠纵行平滑肌自发收缩的力量和频率有相反的影响。最后，用阿普唑仑增强γ2-GABAAR功能可逆转应激诱导的结肠自发收缩力量增加。该研究证明了小鼠结肠内GABAAR系统的分子和功能多样性，为开发基于GABAAR的胃肠疾病治疗方法提供了框架。
