Src Dependent Pancreatic Acinar Injury Can Be Initiated Independent of an Increase in Cytosolic Calcium

Mishra, V and Cline, R and Noel, P and Karlsson, J and Baty, CJ and Orlichenko, L and Patel, K and Trivedi, RN and Husain, SZ and Acharya, C and Durgampudi, C and Stolz, DB and Navina, S and Singh, VP (2013) Src Dependent Pancreatic Acinar Injury Can Be Initiated Independent of an Increase in Cytosolic Calcium. PLoS ONE, 8 (6).

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Abstract

Several deleterious intra-acinar phenomena are simultaneously triggered on initiating acute pancreatitis. These culminate in acinar injury or inflammatory mediator generation in vitro and parenchymal damage in vivo. Supraphysiologic caerulein is one such initiator which simultaneously activates numerous signaling pathways including non-receptor tyrosine kinases such as of the Src family. It also causes a sustained increase in cytosolic calcium- a player thought to be crucial in regulating deleterious phenomena. We have shown Src to be involved in caerulein induced actin remodeling, and caerulein induced changes in the Golgi and post-Golgi trafficking to be involved in trypsinogen activation, which initiates acinar cell injury. However, it remains unclear whether an increase in cytosolic calcium is necessary to initiate acinar injury or if injury can be initiated at basal cytosolic calcium levels by an alternate pathway. To study the interplay between tyrosine kinase signaling and calcium, we treated mouse pancreatic acinar cells with the tyrosine phosphatase inhibitor pervanadate. We studied the effect of the clinically used Src inhibitor Dasatinib (BMS-354825) on pervanadate or caerulein induced changes in Src activation, trypsinogen activation, cell injury, upstream cytosolic calcium, actin and Golgi morphology. Pervanadate, like supraphysiologic caerulein, induced Src activation, redistribution of the F-actin from its normal location in the sub-apical area to the basolateral areas, and caused antegrade fragmentation of the Golgi. These changes, like those induced by supraphysiologic caerulein, were associated with trypsinogen activation and acinar injury, all of which were prevented by Dasatinib. Interestingly, however, pervanadate did not cause an increase in cytosolic calcium, and the caerulein induced increase in cytosolic calcium was not affected by Dasatinib. These findings suggest that intra-acinar deleterious phenomena may be initiated independent of an increase in cytosolic calcium. Other players resulting in acinar injury along with the Src family of tyrosine kinases remain to be explored. © 2013 Mishra et al.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Mishra, V Cline, R Noel, P Karlsson, J jmk64@pitt.edu JMK64 Baty, CJ cjb16@pitt.edu CJB16 Orlichenko, L Patel, K Trivedi, RN Husain, SZ soh14@pitt.edu SOH14 0000-0001-9916-319X Acharya, C Durgampudi, C Stolz, DB donna.stolz@pitt.edu DSTOLZ Navina, S Singh, VP
Contributors:	Contribution Contributors Name Email Pitt Username ORCID Editor Dryer, Stuart E. UNSPECIFIED UNSPECIFIED UNSPECIFIED
Date:	18 June 2013
Date Type:	Publication
Journal or Publication Title:	PLoS ONE
Volume:	8
Number:	6
DOI or Unique Handle:	10.1371/journal.pone.0066471
Schools and Programs:	School of Medicine > Cell Biology and Molecular Physiology School of Medicine > Medicine School of Medicine > Pathology School of Medicine > Pediatrics
Refereed:	Yes
Date Deposited:	15 Jul 2013 20:13
Last Modified:	27 Jan 2019 00:55
URI:	http://d-scholarship.pitt.edu/id/eprint/19211

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