TRPM7 residue S1269 mediates cAMP dependence of Ca²⁺ influx

Abstract

The nonspecific divalent cation channel TRPM7 (transient receptor potential-melastatin-like 7) is involved in many Ca 2+ and Mg 2+ -dependent cellular processes, including survival, proliferation and migration. TRPM7 expression predicts metastasis and recurrence in breast cancer and several other cancers. In cultured cells, it can induce an invasive phenotype by promoting Ca 2+ -mediated epithelialmesenchymal transition. We previously showed that in neuroblastoma cells that overexpress TRPM7 moderately, stimulation with Ca 2+ -mobilizing agonists leads to a characteristic sustained influx of Ca 2+ .Here we report that sustained influx through TRPM7 is abruptly abrogated by elevating intracellular levels of cAMP. Using pharmacological inhibitors and overexpression studies we show that this blockage is mediated by the cAMP effector Protein Kinase A (PKA). Mutational analysis demonstrates that the Serine residue S1269, which is present proximal to the coiled-coil domain within the protein c-terminus, is responsible for sensitivity to cAMP.

Protein Kinase A in cellular migration—Niche signaling of a ubiquitous kinase

“…Transient Receptor Potential (TRP) channels, particularly TRPC6 (Weber et al, 2015;Farmer et al, 2019;Asghar and Törnquist, 2020), TRPV1 (Miyake et al, 2015), TRPV4 (Mrkonjić et al, 2015;Li et al, 2020;Yang et al, 2020;Lakk and Križaj, 2021), and TRPM7 (Clark et al, 2006;Su et al, 2006;Wei et al, 2009;Wang et al, 2014;Broertjes et al, 2019;Lefebvre et al, 2020;Yankaskas et al, 2021) are increasingly recognized as important regulators of cellular migration, as thoughtfully reviewed in (Howe, 2011;Fiorio Pla and Gkika, 2013;Canales et al, 2019). Importantly, all of the aforementioned channels have been shown to be either direct substrates of PKA [TRPV1 (Rathee et al, 2002;Mohapatra and Nau, 2003;Mohapatra and Nau, 2005;Por et al, 2013), TRPV4 (Fan et al, 2009;Cao et al, 2018), TRPC6 (Nishioka et al, 2011;Horinouchi et al, 2012), and likely TRPM7 (Tian et al, 2018;Broertjes et al, 2019)] or regulated downstream of PKA activity (TRPM7 (Takezawa et al, 2004), establishing these and possibly other members of the TRP channel family as important players in PKA-mediated ion flux during migration. Crosstalk between PKA and TRP channels during cell migration has been well documented and is reviewed in (Howe, 2011).…”

Cell death induction and protection by activation of ubiquitously expressed anion/cation channels. Part 3: the roles and properties of TRPM2 and TRPM7

“…In addition, intracellular Mg 2+ was reported to inhibit TRPM7 channel activity by screening the negatively charged PIP 2 (Kozak et al, 2005) and thereby disrupting the PIP 2 -TRPM7 interaction (Zhelay et al, 2018) (Figure 2). Recently, cAMP/PKA was shown to downregulate the TRPM7 activity and expression by phosphorylating TRPM7 at S1269 existing near the CCD region (Tian et al, 2018;Broertjes et al, 2019) (Figure 2). Furthermore, TRPM7 channel activity was demonstrated to be inhibited by ADP-ribosylation factor-like GTPase 15 (ARL15) through forming a macromolecular complex together with TRPM7 and cystathione-β-synthase (CBS)-pair domain divalent metal cation transport mediator (CNNM) (Kollewe et al, 2021;Mahbub et al, 2023).…”