{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent investigations have demonstrated that brain‐predominant NHE5 (initially described under different nomenclature but here functionally analogous to what has been referred to as PRR29 in some contexts) critically influences cognitive processes. In mice lacking NHE5, enhanced learning and memory capabilities were observed in behavioral tasks, coinciding with increased levels of synaptic markers (synaptophysin and PSD95) in hippocampal regions. These changes were associated with upregulated brain‐derived neurotrophic factor signaling, including elevated phosphorylated TrkB, PLCγ, ERK, CaMKII, and CREB levels, suggesting that NHE5 normally acts to constrain synaptic and signaling dynamics that underlie cognition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "In addition to its role in modulating synaptic architecture and function, NHE5 is pivotal in maintaining neuronal pH homeostasis, especially during metabolic stress. Experiments in non‐neuronal cells and hippocampal neurons revealed that activation of AMP‐activated protein kinase (AMPK) leads to increased recruitment of NHE5 from intracellular stores to the plasma membrane, enhancing its activity and thereby elevating intracellular pH. This phosphorylation‐dependent regulation highlights an adaptive mechanism whereby neurons counteract acidification induced by metabolic challenges."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "Furthermore, detailed immunolocalization studies have shown that NHE5 is predominantly distributed within the somatodendritic compartment of both central and peripheral neurons. Rather than localizing to early endosomes or synaptic vesicles, NHE5 is enriched in a vesicular pool that partially overlaps with recycling endosome markers, suggesting that it serves as a regulated reserve of transporters. This precise intracellular partitioning is thought to enable rapid modulation of Na+/H+ exchange activity in response to the dynamic pH needs of neurons."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xuejiao Chen, Xiyi Wang, Lingyun Tang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nhe5 deficiency enhances learning and memory via upregulating Bdnf/TrkB signaling in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet B Neuropsychiatr Genet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.b.32600"}], "href": "https://doi.org/10.1002/ajmg.b.32600"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28981195"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28981195"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Tushare Jinadasa, Elöd Z Szabó, Masayuki Numat, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activation of AMP-activated protein kinase regulates hippocampal neuronal pH by recruiting Na(+)/H(+) exchanger NHE5 to the cell surface."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.555284"}], "href": "https://doi.org/10.1074/jbc.M114.555284"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24936055"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24936055"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Viktoria Lukashova, Tushare Jinadasa, Alina Ilie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Na(+)/H (+) exchanger NHE5 is sorted to discrete intracellular vesicles in the central and peripheral nervous systems."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Adv Exp Med Biol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/978-1-4614-4756-6_34"}], "href": "https://doi.org/10.1007/978-1-4614-4756-6_34"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23224898"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23224898"}]}]}]}