Zonulin receptor complex (EGFR/PAR2 complex)

The Zonulin receptor complex is a multi-protein signaling unit primarily composed of the Epidermal Growth Factor Receptor (EGFR) and Protease-Activated Receptor 2 (PAR2) [1, 2]. Zonulin, identified as the precursor of haptoglobin-2 (pre-HP2), acts as an endogenous ligand that binds to this complex to modulate intestinal paracellular permeability by regulating the assembly and disassembly of tight junctions [3]. Upon binding, zonulin triggers a signaling cascade involving phospholipase C (PLC) and protein kinase C (PKC), leading to the phosphorylation of tight junction proteins like zonula occludens-1 (ZO-1) and subsequent actin polymerization [1, 4]. Dysregulation of this pathway is strongly associated with increased intestinal permeability, often referred to as leaky gut, which plays a critical role in the pathogenesis of autoimmune and inflammatory disorders, including celiac disease and type 1 diabetes [2, 5]. Therapeutic targeting of the zonulin receptor complex aims to restore barrier integrity and prevent the translocation of luminal antigens into the submucosa. Larazotide acetate (AT-1001) is the most prominent drug candidate, acting as a zonulin antagonist that prevents the opening of tight junctions by blocking the interaction between zonulin and its receptor complex [6, 7]. Sources: [1] Fasano A. Physiol Rev. 2011;91(1):151-175. [2] Sturgeon C, Fasano A. Tissue Barriers. 2016;4(4):e1251384. [3] Tripathi A, et al. Proc Natl Acad Sci U S A. 2009;106(39):16799-16804. [4] Valitutti F, Fasano A. Front Endocrinol. 2019;10:351. [5] Wood Heickman LK, et al. Pediatr Diabetes. 2020;21(3):447-455. [6] Gopalakrishnan S, et al. Expert Opin Investig Drugs. 2013;22(12):1665-1672. [7] Leffler DA, et al. Gastroenterology. 2015;148(7):1311-1319.

Other names

Epidermal growth factor receptor/Protease-activated receptor 2 complexPre-haptoglobin 2 receptorZonula occludens toxin receptorZOT receptorEGFR/PAR2 heterodimer

Antagonism of zonulin binding to the receptor complex to prevent tight junction disassembly and reduce pathological intestinal permeability.