Thrombin-Induced Calpain Activation Promotes Protease-Activated Receptor 1 Internalization
The serine protease thrombin activates Protease-Activated Receptors (PARs), a family of G-protein-coupled receptors (GPCRs) activated by the proteolytic cleavage of their extracellular N-terminal domain. Four members of this family have been identified: PAR1–4. The activation of Protease-Activated R...
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Wiley
2017-01-01
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| Series: | International Journal of Cell Biology |
| Online Access: | http://dx.doi.org/10.1155/2017/1908310 |
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| author | Alejandro Alvarez-Arce Irene Lee-Rivera Edith López Arturo Hernández-Cruz Ana María López-Colomé |
| author_facet | Alejandro Alvarez-Arce Irene Lee-Rivera Edith López Arturo Hernández-Cruz Ana María López-Colomé |
| author_sort | Alejandro Alvarez-Arce |
| collection | DOAJ |
| description | The serine protease thrombin activates Protease-Activated Receptors (PARs), a family of G-protein-coupled receptors (GPCRs) activated by the proteolytic cleavage of their extracellular N-terminal domain. Four members of this family have been identified: PAR1–4. The activation of Protease-Activated Receptor 1(PAR1), the prototype of this receptor family, leads to an increase in intracellular Ca+2 concentration ([Ca+2]i) mediated by Gq11α coupling and phospholipase C (PLC) activation. We have previously shown that the stimulation of PAR1 by thrombin promotes intracellular signaling leading to RPE cell transformation, proliferation, and migration which characterize fibroproliferative eye diseases leading to blindness. Within this context, the elucidation of the mechanisms involved in PAR1 inactivation is of utmost importance. Due to the irreversible nature of PAR1 activation, its inactivation must be efficiently regulated in order to terminate signaling. Using ARPE-19 human RPE cell line, we characterized thrombin-induced [Ca+2]i increase and demonstrated the calcium-dependent activation of μ-calpain mediated by PAR1. Calpains are a family of calcium-activated cysteine proteases involved in multiple cellular processes including the internalization of membrane proteins through clathrin-coated vesicles. We demonstrated that PAR1-induced calpain activation results in the degradation of α-spectrin by calpain, essential for receptor endocytosis, and the consequent decrease in PAR1 membrane expression. Collectively, the present results identify a novel μ-calpain-dependent mechanism for PAR1 inactivation following exposure to thrombin. |
| format | Article |
| id | doaj-art-f2e225ec9bc84c2cae94b63afbec9e86 |
| institution | Kabale University |
| issn | 1687-8876 1687-8884 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | International Journal of Cell Biology |
| spelling | doaj-art-f2e225ec9bc84c2cae94b63afbec9e862025-02-03T06:14:03ZengWileyInternational Journal of Cell Biology1687-88761687-88842017-01-01201710.1155/2017/19083101908310Thrombin-Induced Calpain Activation Promotes Protease-Activated Receptor 1 InternalizationAlejandro Alvarez-Arce0Irene Lee-Rivera1Edith López2Arturo Hernández-Cruz3Ana María López-Colomé4Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México City, MexicoInstituto de Fisiología Celular, Universidad Nacional Autónoma de México, México City, MexicoInstituto de Fisiología Celular, Universidad Nacional Autónoma de México, México City, MexicoInstituto de Fisiología Celular, Universidad Nacional Autónoma de México, México City, MexicoInstituto de Fisiología Celular, Universidad Nacional Autónoma de México, México City, MexicoThe serine protease thrombin activates Protease-Activated Receptors (PARs), a family of G-protein-coupled receptors (GPCRs) activated by the proteolytic cleavage of their extracellular N-terminal domain. Four members of this family have been identified: PAR1–4. The activation of Protease-Activated Receptor 1(PAR1), the prototype of this receptor family, leads to an increase in intracellular Ca+2 concentration ([Ca+2]i) mediated by Gq11α coupling and phospholipase C (PLC) activation. We have previously shown that the stimulation of PAR1 by thrombin promotes intracellular signaling leading to RPE cell transformation, proliferation, and migration which characterize fibroproliferative eye diseases leading to blindness. Within this context, the elucidation of the mechanisms involved in PAR1 inactivation is of utmost importance. Due to the irreversible nature of PAR1 activation, its inactivation must be efficiently regulated in order to terminate signaling. Using ARPE-19 human RPE cell line, we characterized thrombin-induced [Ca+2]i increase and demonstrated the calcium-dependent activation of μ-calpain mediated by PAR1. Calpains are a family of calcium-activated cysteine proteases involved in multiple cellular processes including the internalization of membrane proteins through clathrin-coated vesicles. We demonstrated that PAR1-induced calpain activation results in the degradation of α-spectrin by calpain, essential for receptor endocytosis, and the consequent decrease in PAR1 membrane expression. Collectively, the present results identify a novel μ-calpain-dependent mechanism for PAR1 inactivation following exposure to thrombin.http://dx.doi.org/10.1155/2017/1908310 |
| spellingShingle | Alejandro Alvarez-Arce Irene Lee-Rivera Edith López Arturo Hernández-Cruz Ana María López-Colomé Thrombin-Induced Calpain Activation Promotes Protease-Activated Receptor 1 Internalization International Journal of Cell Biology |
| title | Thrombin-Induced Calpain Activation Promotes Protease-Activated Receptor 1 Internalization |
| title_full | Thrombin-Induced Calpain Activation Promotes Protease-Activated Receptor 1 Internalization |
| title_fullStr | Thrombin-Induced Calpain Activation Promotes Protease-Activated Receptor 1 Internalization |
| title_full_unstemmed | Thrombin-Induced Calpain Activation Promotes Protease-Activated Receptor 1 Internalization |
| title_short | Thrombin-Induced Calpain Activation Promotes Protease-Activated Receptor 1 Internalization |
| title_sort | thrombin induced calpain activation promotes protease activated receptor 1 internalization |
| url | http://dx.doi.org/10.1155/2017/1908310 |
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