Faculty Articles

MAPK Activation Patterns of AT1R and CB1R in SHR versus Wistar Astrocytes: Evidence of CB1R Hypofunction and Crosstalk between AT1R and CB1R

Publication Title

Cellular Signalling

Publisher

Elsevier Science Ltd.

ISSN

0898-6568

Publication Date

12-1-2017

Keywords

angiotensin II, angiotensin type 1 receptor, brainstem, cannabinoid type 1 receptor, MAPK, spontaneously hypertensive rat astrocytes

Abstract

BACKGROUND: Angiotensin (Ang) II and cannabinoids regulate physiologically relevant astroglial functions via receptor-mediated activation of Mitogen-activated protein kinases (MAPKs). In this study, we investigated the consequences of astroglial Ang II type 1 receptor (AT1R) and Cannabinoid type 1 receptor (CB1R) activation, alone and in combination, on MAPK activation in the presence and absence of hypertensive states. In addition, we also investigated a novel unidirectional crosstalk mechanism between AT1R and CB1R, that involves PKC-mediated phosphorylation of CB1R.

METHODS: Astrocytes were isolated from the brainstem and cerebellum of Spontaneously hypertensive rats (SHRs) and normotensive Wistar rats. The cells were treated with either 100nM Ang II or 10nM Arachidonyl-2'-chloroethylamide (ACEA), both alone and in combination, for varying time periods, and the extent of phosphorylation of MAPKs, ERK and p38, and the phosphorylated forms of CB1R (p-CB1R), were measured using western blotting.

RESULTS: Ang II treatment resulted in a greater activation of MAPKs in SHR brainstem astrocytes, but not SHR cerebellar astrocytes when compared to Wistar rats. ACEA-mediated MAPK activation was significantly lower in brainstem astrocytes of SHRs when compared to Wistar rats. ACEA negatively modulates AT1R-mediated MAPK activation in both cerebellar and brainstem astrocytes of both models. The effect however was diminished in brainstem astrocytes. Ang II caused a significant increase in phosphorylation of CB1R in cerebellar astrocytes, while its effect was diminished in brainstem astrocytes of both models.

CONCLUSION: Both Ang II and ACEA-induced MAPK activation were significantly altered in SHR astrocytes when compared to Wistar astrocytes. A possible reduction in CB1R functionality, coupled with a hyperfunctional AT1R in the brainstem, could well be significant factors in the development of hypertensive states. AT1R-mediated phosphorylation of CB1R could be critical for impaired cerebellar development characterized by a hyperactive RAS.

DOI

10.1016/j.cellsig.2017.09.002

Volume

40

First Page

81

Last Page

90

Disciplines

Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences

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