Actin Cytoskeleton-dependent Regulation of Corticotropin-releasing Factor Receptor Heteromers

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2017 Jul 14

PMID 28701349

Citations 11

Authors

Burcu Hasdemir

Shilpi Mahajan

Juan Oses-Prieto

Shreya Chand

Michael Woolley

Alma Burlingame

Dimitris K Grammatopoulos

Aditi Bhargava

Affiliations

Soon will be listed here.

Abstract

Stress responses are highly nuanced and variable, but how this diversity is achieved by modulating receptor function is largely unknown. Corticotropin-releasing factor receptors (CRFRs), class B G protein-coupled receptors, are pivotal in mediating stress responses. Here we show that the two known CRFRs interact to form heteromeric complexes in HEK293 cells coexpressing both CRFRs and in vivo in mouse pancreas. Coimmunoprecipitation and mass spectrometry confirmed the presence of both CRFR and CRFβR, along with actin in these heteromeric complexes. Inhibition of actin filament polymerization prevented the transport of CRFβR to the cell surface but had no effect on CRFR. Transport of CRFR when coexpressed with CRFR became actin dependent. Simultaneous stimulation of cells coexpressing CRFR+CRFβR with their respective high-affinity agonists, CRF+urocortin2, resulted in approximately twofold increases in peak Ca responses, whereas stimulation with urocortin1 that binds both receptors with 10-fold higher affinity did not. The ability of CRFRs to form heteromeric complexes in association with regulatory proteins is one mechanism to achieve diverse and nuanced function.

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References

Murat B, Devost D, Andres M, Mion J, Boulay V, Corbani M . V1b and CRHR1 receptor heterodimerization mediates synergistic biological actions of vasopressin and CRH. Mol Endocrinol. 2012; 26(3):502-20. PMC: 5417131. DOI: 10.1210/me.2011-1202. View

Lamaze C, Fujimoto L, Yin H, Schmid S . The actin cytoskeleton is required for receptor-mediated endocytosis in mammalian cells. J Biol Chem. 1997; 272(33):20332-5. DOI: 10.1074/jbc.272.33.20332. View

Milligan G . G protein-coupled receptor hetero-dimerization: contribution to pharmacology and function. Br J Pharmacol. 2009; 158(1):5-14. PMC: 2795239. DOI: 10.1111/j.1476-5381.2009.00169.x. View

Rosenfeld J, Capdevielle J, Guillemot J, Ferrara P . In-gel digestion of proteins for internal sequence analysis after one- or two-dimensional gel electrophoresis. Anal Biochem. 1992; 203(1):173-9. DOI: 10.1016/0003-2697(92)90061-b. View

Alken M, Rutz C, Kochl R, Donalies U, Oueslati M, Furkert J . The signal peptide of the rat corticotropin-releasing factor receptor 1 promotes receptor expression but is not essential for establishing a functional receptor. Biochem J. 2005; 390(Pt 2):455-64. PMC: 1198925. DOI: 10.1042/BJ20050113. View

Reyes T, Lewis K, PERRIN M, Kunitake K, Vaughan J, Arias C . Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proc Natl Acad Sci U S A. 2001; 98(5):2843-8. PMC: 30227. DOI: 10.1073/pnas.051626398. View

Schulz K, Rutz C, Westendorf C, Ridelis I, Vogelbein S, Furkert J . The pseudo signal peptide of the corticotropin-releasing factor receptor type 2a decreases receptor expression and prevents Gi-mediated inhibition of adenylyl cyclase activity. J Biol Chem. 2010; 285(43):32878-32887. PMC: 2963340. DOI: 10.1074/jbc.M110.129627. View

WATKINS K, Roth B, Kroeze W, Gaudreau P, Leclerc N, Descarries L . Similar ultrastructural distribution of the 5-HT(2A) serotonin receptor and microtubule-associated protein MAP1A in cortical dendrites of adult rat. Neuroscience. 2002; 113(1):23-35. DOI: 10.1016/s0306-4522(02)00146-x. View

Levoye A, Dam J, Ayoub M, Guillaume J, Jockers R . Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers. EMBO Rep. 2006; 7(11):1094-8. PMC: 1679777. DOI: 10.1038/sj.embor.7400838. View

10.

Lewis K, Li C, PERRIN M, Blount A, Kunitake K, Donaldson C . Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proc Natl Acad Sci U S A. 2001; 98(13):7570-5. PMC: 34709. DOI: 10.1073/pnas.121165198. View

11.

Gao M, Giamouridis D, Lai N, Walenta E, Paschoal V, Kim Y . One-time injection of AAV8 encoding urocortin 2 provides long-term resolution of insulin resistance. JCI Insight. 2016; 1(15):e88322. PMC: 5033760. DOI: 10.1172/jci.insight.88322. View

12.

Vischer H, Watts A, Nijmeijer S, Leurs R . G protein-coupled receptors: walking hand-in-hand, talking hand-in-hand?. Br J Pharmacol. 2011; 163(2):246-60. PMC: 3087129. DOI: 10.1111/j.1476-5381.2011.01229.x. View

13.

Jan Y, Jan L . A trafficking checkpoint controls GABA(B) receptor heterodimerization. Neuron. 2000; 27(1):97-106. DOI: 10.1016/s0896-6273(00)00012-x. View

14.

Markovic D, Vatish M, Gu M, Slater D, Newton R, Lehnert H . The onset of labor alters corticotropin-releasing hormone type 1 receptor variant expression in human myometrium: putative role of interleukin-1beta. Endocrinology. 2007; 148(7):3205-13. DOI: 10.1210/en.2007-0095. View

15.

Gingras A, Aebersold R, Raught B . Advances in protein complex analysis using mass spectrometry. J Physiol. 2004; 563(Pt 1):11-21. PMC: 1665575. DOI: 10.1113/jphysiol.2004.080440. View

16.

Perrin M, DiGruccio M, Koerber S, Rivier J, Kunitake K, Bain D . A soluble form of the first extracellular domain of mouse type 2beta corticotropin-releasing factor receptor reveals differential ligand specificity. J Biol Chem. 2003; 278(18):15595-600. DOI: 10.1074/jbc.M210476200. View

17.

Hasdemir B, Bunnett N, Cottrell G . Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) mediates post-endocytic trafficking of protease-activated receptor 2 and calcitonin receptor-like receptor. J Biol Chem. 2007; 282(40):29646-57. DOI: 10.1074/jbc.M702974200. View

18.

Trester-Zedlitz M, Burlingame A, Kobilka B, Von Zastrow M . Mass spectrometric analysis of agonist effects on posttranslational modifications of the beta-2 adrenoceptor in mammalian cells. Biochemistry. 2005; 44(16):6133-43. DOI: 10.1021/bi0475469. View

19.

Kalwat M, Thurmond D . Signaling mechanisms of glucose-induced F-actin remodeling in pancreatic islet β cells. Exp Mol Med. 2013; 45:e37. PMC: 3789261. DOI: 10.1038/emm.2013.73. View

20.

Hotta M, Shibasaki T, Arai K, Demura H . Corticotropin-releasing factor receptor type 1 mediates emotional stress-induced inhibition of food intake and behavioral changes in rats. Brain Res. 1999; 823(1-2):221-5. DOI: 10.1016/s0006-8993(99)01177-4. View