Large- pore connexin hemichannels function like molecule transporters independent of ion conduction

• 成果类型: Article
• 署名作者: Gaete, Pablo S.; Kumar, Deepak; Fernandez, Cynthia I.; Capuccino, Juan M. Valdez; Bhatt, Aashish; Jiang, Wenjuan; Lin, Yi - Chun; Liu, Yu; Harris, Andrew L.; Luo, Yun L.; Contreras, Jorge E.
• 署名单位: University of California System; University of California Davis; Western University of Health Sciences; Rutgers University System; Rutgers University New Brunswick; Rutgers University Biomedical & Health Sciences; Rutgers University Newark
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8832
• DOI: 10.1073/pnas.2403903121
• 发表日期: 2024-08-13
• 关键词: gap-junction channels; permeation; permeability; selectivity; mutations; determinant; inhibition; activation; mechanisms; disease

摘要

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 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.