Ponzio Todd A, Wang Yu-Feng, Hatton Glenn I
Department of Cell Biology and Neuroscience, University of California, Riverside, USA.
Am J Physiol Regul Integr Comp Physiol. 2006 Aug;291(2):R359-66. doi: 10.1152/ajpregu.00747.2005. Epub 2006 Apr 27.
Supraoptic nucleus (SON) neurons secrete oxytocin or vasopressin in response to various physiological stimuli (e.g., lactation/suckling, dehydration). Released near fenestrated capillaries of the neurohypophysis, these peptides enter the blood and travel to peripheral target organs. The pervasive neuromodulator adenosine, acting at A1 receptors, is an important inhibitory regulator of magnocellular neuroendocrine cell activity. Another high-affinity adenosine receptor exists in this system, however. We examined the physiological effects of adenosine A2A receptor activation and determined its localization among various cell types within the SON. In whole cell patch-clamp recordings from rat brain slices, application of the selective adenosine A2A receptor agonist CGS-21680 caused membrane depolarizations in SON neurons, often leading to increased firing activity. Membrane potential changes were persistent (>10 min) and could be blocked by the selective A2A receptor antagonist ZM-241385, or GDP-beta-S, the latter suggesting postsynaptic sites of action. However, +/--alpha-methyl-(4-carboxyphenyl)glycine or TTX also blocked CGS-21680 effects, indicating secondary actions on postsynaptic neurons. In voltage-clamp mode, application of CGS-21680 caused a slight increase (approximately 8%) in high-frequency clusters of excitatory postsynaptic currents. With the use of specific antibodies, adenosine A2A receptors were immunocytochemically localized to both the magnocellular neurons and astrocytes of the SON. Ecto-5'nucleotidase, an enzyme involved in the metabolism of ATP to adenosine, was also localized to astrocytes of the SON. These results demonstrate that adenosine acting at A2A receptors can enhance the excitability of SON neurons and modulate transmitter release from glutamatergic afferents projecting to the nucleus. We suggest that adenosine A2A receptors may function in neuroendocrine regulation through both direct neuronal mechanisms and via actions involving glia.
视上核（SON）神经元会响应各种生理刺激（如哺乳/吮吸、脱水）而分泌催产素或血管加压素。这些肽在神经垂体有孔毛细血管附近释放后进入血液，并输送到外周靶器官。普遍存在的神经调质腺苷通过作用于A1受体，是大细胞神经内分泌细胞活动的重要抑制调节因子。然而，该系统中还存在另一种高亲和力腺苷受体。我们研究了腺苷A2A受体激活的生理效应，并确定了其在视上核内不同细胞类型中的定位。在大鼠脑片的全细胞膜片钳记录中，应用选择性腺苷A2A受体激动剂CGS-21680会导致视上核神经元的膜去极化，常常导致放电活动增加。膜电位变化持续存在（>10分钟），并且可被选择性A2A受体拮抗剂ZM-241385或GDP-β-S阻断，后者提示其作用于突触后位点。然而，±α-甲基-（4-羧基苯基）甘氨酸或TTX也能阻断CGS-21680的效应，表明其对突触后神经元有继发性作用。在电压钳模式下，应用CGS-21680会使兴奋性突触后电流的高频簇轻微增加（约8%）。使用特异性抗体，腺苷A2A受体通过免疫细胞化学方法定位到视上核的大细胞神经元和星形胶质细胞。胞外5'-核苷酸酶是一种参与将ATP代谢为腺苷的酶，也定位到视上核的星形胶质细胞。这些结果表明，作用于A2A受体的腺苷可增强视上核神经元的兴奋性，并调节投射到该核的谷氨酸能传入神经递质的释放。我们认为，腺苷A2A受体可能通过直接的神经元机制以及涉及神经胶质细胞的作用在神经内分泌调节中发挥作用。
