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Large-pore connexin hemichannels function like molecule transporters independent of ion conduction.
Gaete, Pablo S; Kumar, Deepak; Fernandez, Cynthia I; Valdez Capuccino, Juan M; Bhatt, Aashish; Jiang, Wenjuan; Lin, Yi-Chun; Liu, Yu; Harris, Andrew L; Luo, Yun L; Contreras, Jorge E.
Afiliação
  • Gaete PS; Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, CA 95616.
  • Kumar D; Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766.
  • Fernandez CI; Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, CA 95616.
  • Valdez Capuccino JM; Department of Pharmacology, Physiology, and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103.
  • Bhatt A; Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766.
  • Jiang W; Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766.
  • Lin YC; Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766.
  • Liu Y; Department of Pharmacology, Physiology, and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103.
  • Harris AL; Department of Pharmacology, Physiology, and Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103.
  • Luo YL; Department of Biotechnology and Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766.
  • Contreras JE; Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, CA 95616.
Proc Natl Acad Sci U S A ; 121(33): e2403903121, 2024 Aug 13.
Article em En | MEDLINE | ID: mdl-39116127
ABSTRACT
Connexin hemichannels were identified as the first members of the eukaryotic large-pore channel family that mediate permeation of both atomic ions and small molecules between the intracellular and extracellular environments. The conventional view is that their pore is a large passive conduit through which both ions and molecules diffuse in a similar manner. In stark contrast to this notion, we demonstrate that the permeation of ions and of molecules in connexin hemichannels can be uncoupled and differentially regulated. We find that human connexin mutations that produce pathologies and were previously thought to be loss-of-function mutations due to the lack of ionic currents are still capable of mediating the passive transport of molecules with kinetics close to those of wild-type channels. This molecular transport displays saturability in the micromolar range, selectivity, and competitive inhibition, properties that are tuned by specific interactions between the permeating molecules and the N-terminal domain that lies within the pore-a general feature of large-pore channels. We propose that connexin hemichannels and, likely, other large-pore channels, are hybrid channel/transporter-like proteins that might switch between these two modes to promote selective ion conduction or autocrine/paracrine molecular signaling in health and disease processes.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Conexinas Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Conexinas Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article