My research interest has been focused on the physiological adaptation of the hypothalamic neuroendocrine cells to different physiological states. The oxytocin (OT) and vasopressin (VP) neurons in the supraoptic nucleus (SON) of the hypothalamus are one of the best models to study such adaptations, because the importance of these hormones and the neuronal responses of the neurons to physiological demands are well documented. The secretions of the neurohypophysial hormones, OT and VP, from the posterior pituitary into the circulation largely depends on the firing patterns of their synthesizing magnocellular neurons (MNCs). The OT and VP neurons show distinct firing patterns during hormone release in response to systemic physiological demands. Preceding each milk ejection, for example, the expression of the firing pattern in OT neurons changes dramatically, characterized as a short and high frequency burst of action potentials. In contrast, VP neurons respond to cardiovascular challenges by increasing their firing rate and adopting a phasic firing pattern comprising alternating periods of activity and silence lasting tens of seconds each. The release and biological effects of OT and VP are believed to be maximized by these distinct firing patterns, the occurrence of which are, therefore, an important part of the response of these neurons to the demand for their respective hormones.
Research in my lab focuses on intrinsic membrane properties that play important roles in shaping the firing patterns that ultimately affect the release of these two hormones. My research utilizes an integrative, multidisciplinary approach combining electrophysiology, Ca++ imaging, immunocytochemistry, and single cell RT-PCR to investigate the intrinsic membrane properties of these neurons.
Project: Epithelial Na+ channels (ENaCs) in the Supraoptic Vasopressin and Oxytocin Neurons
Salt-sensitive individuals have blood pressure that is unusually sensitive to salt intake. Salt-sensitivity increases the risk of death whether or not a person has high blood pressure. Furthermore, salt-sensitive persons are likely to develop high blood pressure as they age. Because salt sensitivity is common in the U.S., it is of significant public health concern. Current interventional approaches counter only the peripheral effects of salt sensitive hypertension, and the results are often unsatisfactory. Therefore, additional therapies that treat the cause of the disorder is needed.
Although the mechanism of salt sensitivity is not well understood, a growing body of evidence suggests that it is caused by, at least partly, an abnormal regulation of the Epithelial Na+ channels (ENaCs) in the brain. Both messengers and proteins for all three ENaC subunits were demonstrated in the rat brain including in vasopressin (VP) and oxytocin (OT) synthesizing magnocellular cells (MNCs) in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei. In addition, a known target for altered ENaC expression, the mineralcorticoid receptor (MR), is present in MNCs.
VP and OT are released from the neurohypophysis into the general circulation. The secretion of VP increases in response to hyperosmolality, hypovolemia, and hypotension, and produces antidiuretic and pressor effects. Plasma OT increases in response to hypernatremia and promote excretion of Na+ (natriuresis).
Because, intracerebroventricular infusion of the ENaC blockers significantly attenuated the hypertension in animal models with salt-sensitive hypertension, these findings strongly suggest that ENaC in MNCs play a significant role in the development of salt-sensitive hypertension. However, the role of ENaCs and their regulation in the brain is not well understood. Therefore, the overall objective of in our research is to characterize the functional significance of ENaCs in MNCs. Our recent study demonstrated that ENaC is a Na+-leak current modulating membrane potential and affecting the frequency action potentials evoked in MNCs. This implies that modulation of ENaC activity is a powerful means to modulate hormone secretions according to physiological demands.
Based on results from our study, dietary Na+ intake affects ENaCs activity and alters the patterns of action potentials in VP and OT MNCs that ultimately affect the secretion of these hormones. Therefore, abnormal regulation of ENaCs in these neurons could contribute to the development of salt-sensitive hypertension. Results from this project will provide critical information concerning central ENaC inhibition as a potential new target in the treatment of cardiovascular disease.
Teruyama R, Sakuraba M, Wilson LL, Wandrey NE, Armstrong WE (2011b) Epithelial Sodium Channels (ENaC) in Magnocellular Cells of the Rat Supraoptic and Paraventricular Nuclei. Am J Physiol Endocrinol Metab. ePub ahead of print.
Teruyama R, Sakuraba M, Kurotaki H, Armstrong WE (2011a) Transient receptor potential channel m4 and m5 in magnocellular cells in rat supraoptic and paraventricular nuclei. J Neuroendocrinol 23:1204-1213.
Del Negro CA, Hayes JA, Pace RW, Brush BR, Teruyama R, Feldman JL (2010) Synaptically activated burst-generating conductances may underlie a group-pacemaker mechanism for respiratory rhythm generation in mammals. Prog Brain Res 187:111-136.
Armstrong, W.E., Wang L., Li C., Teruyama, R. Performance, properties, and plasticity of identified oxytocin and vasopressin neurons in vitro. J Neuroendocrinol. 2010 Feb; 22:330-342
Teruyama, R, Lipschitz D, Wang L, Ramoz GR, Crowley WR, Bealer SL, Armstrong W. Central blockade of oxytocin receptors during mid-late gestation reduces the amplitude of slow afterhyperpolarization in the supraoptic oxytocin neurons. Am J Physiol Endocrinol Metab. 2008 Nov; 295(5): E1167-71. Epub 2008 Sep 23.
Teruyama, R. and Armstrong, W.E. Calcium-dependent fast depolarizing afterpotentials in vasopressin neurons in the rat supraoptic nucleus. J Neurophysiol. 2007 Nov;98(5):2612-21. Epub 2007 Aug 22.
Armstrong, WE., Rubrum, A., Teruyama, R., Bond, CT., and Adelman, JP. Immunocytochemical localization of small-conductance, Calcium-dependent potassium channels in astrocytes of the rat supraoptic nucleus. J. Comp. Neurol. 2005 491:175-185
Teruyama, R., and Armstrong, WE. Enhancement of calcium-dependent afterpotentials in oxytocin neurons of the rat supraoptic nucleus during lactation. J Physiol. 2005 Jul 15:566(Pt 2):505-18. Epub 2005 May 5.
Teruyama, R., and Armstrong, W.E. Changes in the active membrane properties of rat supraoptic neurones during pregnancy and lactation. J Neuroendocrinol. 2002 Dec 14(12):933-44.
Armstrong, W.E., Stern, J.E., and Teruyama, R. Plasticity in the electrophysiological properties of oxytocin neurons. Microsc Res Tech. 2002 Jan 15; 56(2):73-80. Review.