Gajić Bojić Milica, Aranđelović Jovana, Škrbić Ranko, Savić Miroslav M
Faculty of Medicine, Center for Biomedical Research, University of Banja Luka, Banja Luka 78000, Republic of Srpska, Bosnia and Herzegovina; Department of Pharmacology, Toxicology and Clinical Pharmacology, University of Banja Luka - Faculty of Medicine, Banja Luka 78000, Republic of Srpska, Bosnia and Herzegovina.
Department of Pharmacology, University of Belgrade - Faculty of Pharmacy, Belgrade 11000, Serbia.
Pharmacol Ther. 2025 Feb;266:108759. doi: 10.1016/j.pharmthera.2024.108759. Epub 2024 Nov 28.
The role of γ- aminobutyric acid (GABA) and GABA receptors is not only essential for neurotransmission in the central nervous system (CNS), but they are also involved in communication in various peripheral tissues such as the pancreas, liver, kidney, gastrointestinal tract, trachea, immune cells and blood vessels. GABA receptors located outside the CNS ("peripheral GABA receptors") enable both neuronal and non-neuronal GABA-ergic signaling in various physiological processes and are generally thought to have similar properties to the extrasynaptic receptors in the CNS. By activating these peripheral receptors, GABA and various GABA receptor modulators, including drugs such as benzodiazepines and general anesthetics, may contribute to or otherwise affect the maintenance of general body homeostasis. However, the existing data in the literature on the role of non-neuronal GABA-ergic signaling in insulin secretion, glucose metabolism, renal function, intestinal motility, airway tone, immune response and blood pressure regulation are far from complete. In fact, they mainly focus on the identification of components for the local synthesis and utilization of GABA and on the expression repertoire of GABA receptor subunits rather than on subunit composition, activation effects and (sub)cellular localization. A deeper understanding of how modulation of peripheral GABA receptors can have significant therapeutic effects on a range of pathological conditions such as multiple sclerosis, diabetes, irritable bowel syndrome, asthma or hypertension could contribute to the development of more specific pharmacological strategies that would provide an alternative or complement to existing therapies. Selective GABA receptor modulators with improved peripheral efficacy and reduced central side effects would therefore be highly desirable first-in-class drug candidates. This review updates recent advances unraveling the molecular components and cellular determinants of the GABA signaling machinery in peripheral organs, tissues and cells of both, humans and experimental animals.
γ-氨基丁酸（GABA）及其受体的作用不仅对中枢神经系统（CNS）的神经传递至关重要，还参与了胰腺、肝脏、肾脏、胃肠道、气管、免疫细胞和血管等各种外周组织的通讯。位于中枢神经系统之外的GABA受体（“外周GABA受体”）在各种生理过程中实现神经元和非神经元的GABA能信号传导，一般认为其性质与中枢神经系统中的突触外受体相似。通过激活这些外周受体，GABA和各种GABA受体调节剂，包括苯二氮卓类药物和全身麻醉剂等，可能有助于或影响全身内环境稳态的维持。然而，文献中关于非神经元GABA能信号在胰岛素分泌、葡萄糖代谢、肾功能、肠道蠕动、气道张力、免疫反应和血压调节中的作用的现有数据远未完整。事实上，这些数据主要集中在GABA的局部合成和利用成分的鉴定以及GABA受体亚基的表达谱，而非亚基组成、激活效应和（亚）细胞定位。深入了解外周GABA受体的调节如何对一系列病理状况（如多发性硬化症、糖尿病、肠易激综合征、哮喘或高血压）产生显著治疗效果，可能有助于开发更具特异性的药理策略，为现有疗法提供替代或补充。因此，具有更高外周效力和更低中枢副作用的选择性GABA受体调节剂将是非常理想的一类新药候选物。本综述更新了在人类和实验动物的外周器官、组织和细胞中揭示GABA信号传导机制的分子成分和细胞决定因素的最新进展。
