CALL FOR PAPERS Neurophypophyseal Hormones: From Genomics and Physiology to Disease Activation of adenosine A2A receptors alters postsynaptic currents and depolarizes neurons of the supraoptic nucleus

Ponzio, Todd A., Yu-Feng Wang, and Glenn I. Hatton. Activation of adenosine A2A receptors alters postsynaptic currents and depolarizes neurons of the supraoptic nucleus. Am J Physiol Regul Integr Comp Physiol 291: R359–R366, 2006. First published April 27, 2006; doi:10.1152/ajpregu.00747.2005.—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-S, the latter suggesting postsynaptic sites of action. However, -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 ( 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.