Angiotensin-Receptor-Associated Protein Modulates Ca2+ Signals in Photoreceptor and Mossy Fiber cells

Rene Barro-Soria,Frank Kirchhoff,Olaf Strauß,Gabriel Knop,Herbert Jägle,Andrea Dannullis,Laura Merkel,Kaspar Gierke,Na Zhao,Hayo Castrop,Johann Helmut Brandstätter,Andreas Feigenspan,Alejandro Caicedo

doi:10.1038/s41598-019-55380-8

Abstract

Fast, precise and sustained neurotransmission requires graded Ca2+ signals at the presynaptic terminal. Neurotransmitter release depends on a complex interplay of Ca2+ fluxes and Ca2+ buffering in the presynaptic terminal that is not fully understood. Here, we show that the angiotensin-receptor-associated protein (ATRAP) localizes to synaptic terminals throughout the central nervous system. In the retinal photoreceptor synapse and the cerebellar mossy fiber-granule cell synapse, we find that ATRAP is involved in the generation of depolarization-evoked synaptic Ca2+ transients. Compared to wild type, Ca2+ imaging in acutely isolated preparations of the retina and the cerebellum from ATRAP knockout mice reveals a significant reduction of the sarcoendoplasmic reticulum (SR) Ca2+-ATPase (SERCA) activity. Thus, in addition to its conventional role in angiotensin signaling, ATRAP also modulates presynaptic Ca2+ signaling within the central nervous system.

Highlights

The retina expresses its own intraretinal renin-angiotensin-system (RAS) that includes all metabolites and proteases such as renin or angiotensin-converting enzyme[1]
As previously reported[30], weak AT1R immunostaining by an antibody that gives no signal in AT1R knockout mouse kidney is seen in the retinal pigment epithelium but is absent from the outer plexiform layer (OPL) (Fig. 1d), suggesting that in the OPL angiotensin-receptor-associated protein (ATRAP) is not involved in conventional angiotensin receptor signaling
While studying the functional role of ATRAP in the retina to further understand the physiological role of the RAS in the retina, we found that ATRAP shapes synaptic Ca2+ transients through mechanisms not involving classical AT1R signaling

Summary

Introduction

The retina expresses its own intraretinal renin-angiotensin-system (RAS) that includes all metabolites and proteases such as renin or angiotensin-converting enzyme[1]. Cells in the retina that express AngII receptors form the signal processing network that is regulated by RAS. In the retinal pigment epithelium (RPE) ATRAP has been shown to play a role in the Ca2+ store-dependent Ca2+ signaling, as well as in modulating AT1R-evoked Ca2+ through activation of TRPV2 channels[6]. Given the expression of ATRAP and SERCA2 in the photoreceptor cells, studying the role of ATRAP in the retina provides insights into RAS-mediated retinal function, in the photoreceptor synapse. We found that ATRAP localizes to the synapses of both rod and cone photoreceptors in the retina and showed abundant expression in other regions of the central nervous system such as the cerebellum. Our data demonstrate a novel physiological function for ATRAP in the presynaptic terminals of photoreceptors and mossy fibers of the cerebellum, where it modulates depolarization-evoked Ca2+ signals

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