Atomistic Insights of Calmodulin Gating of Complete Ion Channels

Abstract

Intracellular calcium is essential for many physiological processes, from neuronal signaling and exocytosis to muscle contraction and bone formation. Ca2+ signaling from the extracellular medium depends both on membrane potential, especially controlled by ion channels selective to K+, and direct permeation of this cation through specialized channels. Calmodulin (CaM), through direct binding to these proteins, participates in setting the membrane potential and the overall permeability to Ca2+. Over the past years many structures of complete channels in complex with CaM at near atomic resolution have been resolved. In combination with mutagenesis-function, structural information of individual domains and functional studies, different mechanisms employed by CaM to control channel gating are starting to be understood at atomic detail. Here, new insights regarding four types of tetrameric channels with six transmembrane (6TM) architecture, Eag1, SK2/SK4, TRPV5/TRPV6 and KCNQ1–5, and its regulation by CaM are described structurally. Different CaM regions, N-lobe, C-lobe and EF3/EF4-linker play prominent signaling roles in different complexes, emerging the realization of crucial non-canonical interactions between CaM and its target that are only evidenced in the full-channel structure. Different mechanisms to control gating are used, including direct and indirect mechanical actuation over the pore, allosteric control, indirect effect through lipid binding, as well as direct plugging of the pore. Although each CaM lobe engages through apparently similar alpha-helices, they do so using different docking strategies. We discuss how this allows selective action of drugs with great therapeutic potential.

The effect of Rhodococcus rhodochrous supplementation on black soldier fly (Diptera: Stratiomyidae) development, nutrition, and waste conversion

“…In addition to these data, calmodulin was found significantly expressed in black soldier fly larvae with R. rhodochrous supplementation. Calmodulin binds calcium and has been implicated in inflammation, metabolism, and smooth muscle contraction (Nunez et al, 2020). Calcium is also required in many cases for initiation of DNA synthesis (Martelly et al, 1983).…”

Cas9-mediated Genome Editing Reveals a Significant Contribution of Calcium Signaling Pathways to Anhydrobiosis in Pv11

“…In the anhydrobiotic tardigrade, Hypsibius dujardini, a calmodulin inhibitor (J-8) and a calcium release modulator (2-APB) reduced the survival rate after rehydration, but the inhibitors against CaN and CaMK had no effect on the anhydrobiotic ability. Given that calmodulin regulates the gating of calcium ion channel in endoplasmic reticulum and mitochondrion as well as the signaling pathways 69,70 , the J-8 and 2-APB treatments may disrupt calcium storage in the organelles rather than calcium signalings, leading to malfunction of those intracellular organelles 71,72 . RNAi-based screening using the nematode Panagrolaimus superbus, showed that knockdown of “CAMK/CAMKL/MELK protein kinase” decreased the survival rate after rehydration 68 , whereas the contribution of CaN - NFAT pathway or CREB on the anhydrobiotic ability was not assessed.…”

KV7.2 kanala: estruktura, erregulazioa eta kitzikagarritasun neuronalean duen ekintza

“…Tetrameroaren estruktura osoa ikusita, trukaturiko tentsioa detektatzeko eremua duela nabaritzen da. Hau da, tentsioa detektatzeko eremuaren ondoan, alboko azpiunitatearen poro-domeinua dauka (2. irudia [35][36][37]).…”