Biological complexity: gating calcium signals (Introduction)

by David Turell , Wednesday, November 15, 2023, 18:49 (164 days ago) @ David Turell

A double lock mechanism:

https://www.the-scientist.com/news/a-double-lock-gates-calcium-signaling-71485

Now, an international collaboration led to two papers published in Science Signaling on the mechanisms that open calcium floodgates, revealing a potential route to novel therapies while settling a debate along the way.

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).

“NAADP is a very curious second messenger,” said Jonathan Marchant, a cell biologist at Medical College of Wisconsin and coauthor on the papers. Although a potent trigger for calcium release, researchers never discovered a direct binding site, or keyhole, for NAADP on TPC. Then, two papers published in 2021, including one from Marchant’s team, provided a missing link.7,8 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.

Comment: again, an example of IC. All parts must work together from the beginning to create the function.