Biochemical controls: ion gate controls (Introduction)

by David Turell , Monday, November 13, 2023, 21:03 (374 days ago) @ David Turell

For calcium and also sodium:

https://www.thepamperedpup.com/halo-collar-gps-smart-dog-fence-review/

"Ion channels expressed on organelles act like gatekeepers, controlling the passage of calcium from internal stores into the cytosol. Nicotinic acid adenine dinucleotide phosphate (NAADP) is one of many keys that unlock the gate. First discovered in the late 1980s in sea urchin eggs and later found in mammalian cells, NAADP triggers calcium release from lysosomal stores via ion channel activation, specifically a two-pore channel (TPC).

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"The studies revealed the molecular identity of a protein, Jupiter microtubule-associated homolog 2 (JPT2), that facilitates NAADP binding to TPC. If NAADP is the handle of the key, then JPT2 is like the blade that slots into the TPC to open its floodgates.

"Adding to the excitement in the field, another paper published later that year identified another blade—the protein like-Sm protein 12 (LSM12)—that linked NAADP to the TPC.

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“'The remarkable thing about this latest paper by Marchant's group is they seem to suggest that you need both JTP2 and LSM12 to bind NAADP and interact with the channel to open it,” said Antony Galione, a pharmacologist at the University of Oxford who was not involved in the study. “One binding protein loaded up with NAADP is not enough, which is quite controlled regulation, really.” Thus, TPC have a double lock system in place to gate NAADP-dependent activities. TPC are just as curious as NAADP. Scientists long believed that ion selectivity was an immutable characteristic of ion channels. However, scientists discovered that TPC also regulate sodium via the direct binding of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2).

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"There is growing evidence that TPC are important for or dysfunctional in infectious diseases, fatty liver disease, and Parkinson’s disease.12 “Maybe we can bypass these binding proteins with our drugs,” said Patel. “In other words, if the binding proteins were defective in some way, let's say disease, then because we've worked out that these chemical activators can bypass these binding proteins, we could potentially correct any defects with these drugs.”

"In addition to exploring the druggable potential of these channels and binding proteins, Marchant is excited to dissect how, at the molecular level, the two proteins interact with NAADP and the TPC, and even each other. “There are some surprising properties of these proteins that we haven’t quite wrapped our heads around yet,” said Marchant."

Comment: the deeper we get into cell membrane complexities the more intricate are the design details. Not by chance. And it can help us correct biochemical errors causing disease.