G-protein-mediated signaling

Group leader: Nina Wettschureck
PhD Students: Jingchen Shao, Tianpeng Wang, Jeonghyeon Kwon, Niharika Shiva, Shamit Kumar
Technical Assistant: Martina Winkels

Our group studies all aspects of cell communication in the vessel wall, for example the regulation of leukocyte/endothelial interactions, the interplay between endothelial cells and smooth muscle cells, and the communication between vascular cells and stromal/parenchymal cells. Most of our projects focus on the large family of G-protein-coupled receptors (GPCRs), which mediate the intracellular effects of numerous hormones, neurotransmitters, or local mediators. In the past, we identified new functions for GPCRs and their effector families G_12/13 and G_q/11 in the cardiovascular, endocrine, and immune system (for example Herroeder et al., Immunity 2009; Sassmann et al., J Clin Invest 2010; Takefuji et al., Circulation 2012; Takefuji et al., J Exp Med 2013; Sivaraj et al., Dev Cell 2013; Chen et al., J Clin Invest 2014; Kaur et al., Circ Res 2016). More recently, we focus on orphan GPCRs, i.e. GPCRs with yet unknown endogenous ligand and function. To better understand the biological function of these enigmatic GPCRs, we performed single-cell expression analyses in primary murine vascular and immune cells (Kaur et al., Nat Commun 2017; Tischner et al., JCI Insight 2017) and identified rare cell populations with specific GPCR repertoires. Based on these data, we are currently analyzing the function of orphan GPCRs in specialized subpopulations of smooth muscle (Carvalho et al., Circulation 2020), endothelial cells and immune cells (Gurusamy et al., Nat Commun 2021, accepted). Other projects address the role of angiocrine factors in cardiac remodeling or the regulation of leukocyte/endothelial interactions.

 

Selected references

Gurusamy M, Tischner D, Shao J, Klatt S, Zukunft S, Bonnavion R, Günther S, Siebenbrodt K, Kestner RI, Kuhlmann T, Fleming I, Offermanns S, Wettschureck N (2021): G-protein-coupled receptor P2Y10 mediates facilitation of chemokine-induced CD4 T cell migration through autocrine/paracrine mediators. Nat Commun, 12(1):6798.

Carvalho J, Chennupati R, Li R, Günther S, Kaur H, Zhao W, Tonack S, Kurz M, Mößlein N, Bünemann M, Offermanns S, Wettschureck N (2020). Orphan G-protein-coupled receptor GPRC5B controls smooth muscle contractility and differentiation by inhibiting prostacyclin receptor signaling. Circulation 141(14):1168-83.

Tischner D, Grimm M, Kaur H, Staudenraus D, Carvalho J, Looso M, Günther S, Wanke F, Moos S, Siller N, Breuer J, Schwab N, Zipp F, Waisman A, Kurschus FC, Offermanns S, Wettschureck N (2017): Single-cell profiling reveals GPCR heterogeneity and functional patterning during neuroinflammation. JCI Insight 3;2(15), doi: 10.1172.

Kaur H, Carvalho J, Looso M, Singh P, Chennupati R, Preussner J, Günther S, Albarrán-Juárez J, Tischner D, Classen S, Offermanns S, Wettschureck N (2017): Single-cell profiling reveals heterogeneity and functional patterning of GPCR expression in the vascular system. Nat Commun 8:15700; DOI: 10.1038.

Kaur H, Takefuji M, Ngai C, Carvalho J, Bayer J, Wietelmann A, Poetsch A, Holper S, Conway SJ, Mollmann H, Looso M, Troidl C, Offermanns S, Wettschureck N (2016): Targeted Ablation of Periostin-Expressing Activated Fibroblasts Prevents Adverse Cardiac Remodeling in Mice. Circ Res. 118:1906-17.

Chen H, Assmann JC, Krenz A, Rahman M, Grimm M, Karsten CM, Kohl J, Offermanns S, Wettschureck N*, and Schwaninger M* (2014): Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate's protective effect in EAE. J Clin Invest 124:2188-92. (*contributed equally)

Sivaraj KK, Takefuji M, Schmidt I, Adams RH, Offermanns S, and Wettschureck N (2013): G13 controls angiogenesis through regulation of VEGFR-2 expression. Dev Cell 25:427-34.

Takefuji M, Kruger M, Sivaraj KK, Kaibuchi K, Offermanns S, and Wettschureck N (2013): RhoGEF12 controls cardiac remodeling by integrating G protein- and integrin-dependent signaling cascades. J Exp Med 210:665-73.

Takefuji M, Wirth A, Lukasova M, Takefuji S, Boettger T, Braun T, Althoff T, Offermanns S, and Wettschureck N (2012): G13-mediated signaling pathway is required for pressure overload-induced cardiac remodeling and heart failure. Circulation 126:1972-82.

Sassmann A, Gier B, Grone HJ, Drews G, Offermanns S, and Wettschureck N (2010): The Gq/G11-mediated signaling pathway is critical for autocrine potentiation of insulin secretion in mice. J Clin Invest 120:2184-93.

Herroeder S, Reichardt P, Sassmann A, Zimmermann B, Jaeneke D, Hoeckner J, Hollmann MW, Fischer KD, Vogt S, Grosse R, Hogg N, Gunzer M, Offermanns S, Wettschureck N (2009): Guanine nucleotide-binding proteins of the G12 family shape immune functions by controlling CD4+ T cell adhesiveness and motility. Immunity 30:708-20.