Direct evidence of intracrine angiotensin II signaling in neurons

Elena Deliu, G. Cristina Brailoiu, Satoru Eguchi, Nicholas E. Hoffman, Joseph E. Rabinowitz, Douglas G. Tilley, Muniswamy Madesh, Walter J. Koch, Eugen Brailoiu

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


The existence of a local renin-angiotensin system (RAS in neurons was first postulated 40 years ago. Further studies indicated intraneuronal generation of ANG II. However, the function and signaling mechanisms of intraneuronal ANG II remained elusive. Since ANG II type 1 receptor (AT1R is the major type of receptor mediating the effects of ANG II, we used intracellular microinjection and concurrent Ca2+ and voltage imaging to examine the functionality of intracellular AT1R in neurons. We show that intracellular administration of ANG II produces a dose-dependent elevation of cytosolic Ca2+ concentration ([Ca2+]i in hypothalamic neurons that is sensitive to AT1R antagonism. Endolysosomal, but not Golgi apparatus, disruption prevents the effect of microinjected ANG II on [Ca2+]i. Additionally, the ANG II-induced Ca2+ response is dependent on microautophagy and sensitive to inhibition of PLC or antagonism of inositol 1,4,5-trisphosphate receptors. Furthermore, intracellular application of ANG II produces AT1R-mediated depolarization of hypothalamic neurons, which is dependent on [Ca2+]i increase and on cation influx via transient receptor potential canonical channels. In summary, we provide evidence that intracellular ANG II activates endolysosomal AT1Rs in hypothalamic neurons. Our results point to the functionality of a novel intraneuronal angiotensinergic pathway, extending the current understanding of intracrine ANG II signaling.

Original languageEnglish (US)
Pages (from-to)C736-C744
JournalAmerican Journal of Physiology - Cell Physiology
Issue number8
StatePublished - Apr 15 2014
Externally publishedYes


  • Calcium
  • Endoplasmic reticulum
  • Renin-angiotensin system

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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