{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHuman RHCG forms a trimeric complex that functions as a crucial ammonia channel. High‐resolution structural studies have revealed that each monomer contains 12 transmembrane helices, with an extended pore architecture optimized for NH3 transport, a process essential to ammonia excretion and renal pH regulation. Functional investigations in kidney and other epithelial cells demonstrated that RHCG facilitates fast, low‐energy–dependent, bi‐directional movement of ammonia, a capacity that is evident when the purified protein is reconstituted in proteoliposomes and when expressed in heterologous systems. In addition, in airway epithelia, RHCG shows apical localization and operates through a saturable mechanism to regulate NH3 flux."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMolecular investigations have further refined our understanding of RHCG’s transport mechanism. Studies using heterologous expression systems corroborate that RHCG mediates the passage of both NH3 and NH4+, with precise subcellular localization in human renal epithelia suggesting predominant apical expression. Computational approaches, including molecular dynamics and quantum mechanical simulations, indicate that conserved residues such as the signature histidine and specific pore-lining phenylalanines contribute to a mechanism in which NH4+ is recruited and deprotonated to yield NH3 that subsequently diffuses through the channel. Moreover, RHCG appears functionally integrated with proton-ATPase complexes in renal intercalated cells, potentially modulating urinary acidification. Site-directed mutagenesis has identified key amino acid residues required for optimal NH3 flux across membranes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in gas transport, RHCG has emerged as a critical player in cancer biology. In esophageal squamous cell carcinoma, cervical cancer, and head and neck squamous cell carcinoma, downregulation of RHCG is associated with aggressive tumor features, including poor differentiation, enhanced invasion, and metastasis, suggesting a tumor-suppressive function. Mechanistic studies indicate that RHCG can stabilize inhibitory proteins (such as IκB), thereby preventing NF-κB activation, and modulate the expression of matrix metalloproteinases and other signaling effectors to impede cancer cell proliferation and motility. Conversely, in gastric adenocarcinoma, elevated RHCG expression correlates with adverse clinicopathological parameters including high HER-2 levels and poor prognosis, highlighting its complex, tissue-specific role in tumor progression and signaling modulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Franz Gruswitz, Sarika Chaudhary, Joseph D Ho, et al. 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