Communication between cells is essential for the proper functioning of the organism, and one of the ways this happens is through tiny channels called gap junctions. These channels are regulated by two different mechanisms: a chemical gate and a voltage-sensitive gate. A recent study by Professor Camillo Peracchia of the University of Rochester, published in the International Journal of Molecular Sciences, explores how these mechanisms work together to control the flow of information between cells, offering new insights into this complex process.
Cells use gap junctions to share important signals and molecules with each other. These channels are especially sensitive to changes in calcium levels within cells and to the electrical voltage across cell membranes. When conditions change, these factors cause the channels to open or close via either the chemical gate or the voltage-sensitive gate. Professor Peracchia’s research suggests that the chemical gate is controlled by a protein called calmodulin, which plays a crucial role in many cellular activities. The voltage-sensitive gate, on the other hand, is primarily made up of a part of the protein called the NH2 terminal domain.
As Professor Peracchia explains, “The chemical gate closes at elevated calcium levels inside the cell and at specific voltage conditions across the cell membrane.” This means that the chemical gate reacts slowly but completely, closing the channel when these specific signals are detected. Meanwhile, the voltage-sensitive gate acts more quickly but does not completely close the channel, making smaller adjustments to the degree of channel opening. The study also reveals that the way these gates respond can change depending on the specific type of connexin protein involved, showing the intricate balance between chemical and electrical signals in controlling these channels.
Professor Peracchia further emphasized that “cytosolic acidification alters the sensitivity of the fast voltage-sensitive gate in an opposite way: it increases the sensitivity of the gate in some cases and decreases it in others.” This double-gating system ensures that cells remain connected under normal conditions, but can quickly disconnect if the cell is under stress, such as during injury or when calcium levels rise.
The study highlights the important role of calmodulin in regulating gap junctions, proposing that the calmodulin lobe acts as a “cork” that can plug the channel from opening during chemical activation. This “cork” model, as described by Professor Peracchia, suggests that the interaction between calmodulin and the channel is influenced by both calcium levels and voltage, providing a dual method of control. He also noted: “Gap junction channels possess two gates that respond to changes in the cell’s internal chemistry and electrical environment.” This model helps to clarify how gap junctions adapt to changes in the body, with potential implications for the development of new treatments for diseases in which cell communication is disrupted.
The research also looks at how these findings could impact various parts of the body, including the heart, liver and brain, where different types of connexin proteins are found. The study highlights that the way these channels behave can vary depending on the specific connexins involved, which are influenced by their unique sensitivity to chemical and electrical signals.
Finally, Professor Peracchia’s research provides valuable insights into how these double-gated mechanisms in gap junction channels are carefully regulated to maintain proper communication between cells. The findings open the door for future research to explore potential treatments that could fine-tune gap junctions under conditions where cell communication is impaired.
Journal reference
Peracchia, C. “Tight junction channel regulation: a tale of two gates: voltage sensitivity of chemical gate and chemical sensitivity of fast voltage gate”. International Journal of Molecular Sciences, 2024. DOI: https://doi.org/10.3390/ijms25020982
About the author
Camilo Peracchia is professor emeritus of pharmacology and physiology at the University of Rochester. In 1962 he received the M.D. degree summa cum laude from the University of Milan, Italy. His research has focused on the regulation of cell-cell communication through gap junction channels. In 1967 he received the U.S. Educational Council Certificate for Foreign Medical Graduates. He has published over one hundred articles, edited three books, and written two. He has been an invited speaker at over forty international conferences and symposia and has been an associate editor of the Journal of Neurocytology. In 1994 he was elected an honorary member of the Società di Medicina e Scienze Naturali (University of Parma, Italy). He has served as a member of the Section for the Study of Cell Biology and Physiology (CBY-1, NIH, 1990-94). He is a member of Marquis Who's Who. He has taught respiratory physiology to medical students and cell biology to graduate students. He has been Director of the Physiology-500 Course (1985-88 and 1998-99), Director of the Respiratory Physiology Section (1986-99) and Co-Leader of the Respiratory Physiology Section in the “Human Structure-Function” Course (2000-04). For his teaching he has been awarded the Manuel D. Goldman Prize (1998), the Edward F. Adolph Medal (2004) and five distinctions.
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