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 Ca2+ and Mg2+-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 Ca2+-mediated epithelial-mesenchymal transition. We previously showed that in neuroblastoma cells that overexpress TRPM7 moderately, stimulation with Ca2+-mobilizing agonists leads to a characteristic sustained influx of Ca2+. Here we report that sustained influx through TRPM7 is abruptly abrogated by elevating intracellular levels of cyclic adenosine monophosphate (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 ).…”

TRPM7 activation potentiates SOCE in enamel cells but requires ORAI

“…This difference between gene expression levels and potentiation of Ca 2+ influx is unclear, but could be linked to the buffering capacity of SOCE by mitochondria [43], as mitochondria are more abundant in maturation stage cells [44] and therefore could sequester a higher Ca 2+ load. Alternatively, Broertjes et al, [45] showed that overexpression of TRPM7 increases Ca 2+ influx when associated with upregulation of second messengers (PKC and PKA). We also analyzed the possible effects of naltriben (100 μM) in [Ca 2+ ] cyt clearance (Fig.…”

Control of TRPM3 Ion Channels by Protein Kinase CK2-Mediated Phosphorylation in Pancreatic β-Cells of the Line INS-1

“…However, only little is known about the phosphorylation of TRPM channels. For TRPM7, it has been shown that gating is inhibited by protein kinase A due to the phosphorylation of the residue S 1269 c-terminal to the coiled coil domain [ 31 ]. For TRPM4 channels, the Ca 2+ sensitivity has been shown to be regulated by protein kinase C–dependent phosphorylation at S 1152 and S 1145 within the C-terminus of the protein [ 32 ] and that casein kinase 1 (CK1)–mediated phosphorylation of S 839 is responsible for the basolateral localization of this channel in polarized epithelial cells [ 33 ].…”