title: The TRPM7 channel kinase regulates store-operated calcium entry.
abstract: Pharmacological and molecular inhibition of transient receptor potential melastatin 7 (TRPM7) reduces store-operated calcium entry (SOCE). Overexpression of TRPM7 in TRPM7-/-cells restores SOCE. TRPM7 is not a store-operated calcium channel. TRPM7 kinase rather than channel modulates SOCE. TRPM7 channel activity contributes to the maintenance of store Ca2+levels at rest.
  
  
  
  The transient receptor potential melastatin 7 (TRPM7) is a protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain. In the present study, we report store-operated calcium entry (SOCE) as a novel target of TRPM7 kinase activity. TRPM7-deficient chicken DT40 B lymphocytes exhibit a strongly impaired SOCE compared to wild-type cells as a result of reduced calcium release activated calcium currents, and independently of potassium channel regulation, membrane potential changes or changes in cell-cycle distribution. Pharmacological blockade of TRPM7 with NS8593 or waixenicin A in wild-type B lymphocytes results in a significant decrease in SOCE, confirming that TRPM7 activity is acutely linked to SOCE, without TRPM7 representing a store-operated channel itself. Using kinase-deficient mutants, we find that TRPM7 regulates SOCE through its kinase domain. Furthermore, Ca2+influx through TRPM7 is essential for the maintenance of endoplasmic reticulum Ca2+concentration in resting cells, and for the refilling of Ca2+stores after a Ca2+signalling event. We conclude that the channel kinase TRPM7 and SOCE are synergistic mechanisms regulating intracellular Ca2+homeostasis.
authors.affiliation: Centre for Biomedical Research, The Queen's Medical Centre, University of Hawaii Cancer Centre and John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
authors.forename: Malika
authors.initials: M
authors.lastname: Faouzi
authors.affiliation: Centre for Biomedical Research, The Queen's Medical Centre, University of Hawaii Cancer Centre and John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kilch
authors.affiliation: Laboratory of Marine Biological Chemistry, Department of Natural Sciences, Hawaii Pacific University, Kaneohe, HI, USA.
authors.forename: F David
authors.initials: FD
authors.lastname: Horgen
authors.affiliation: Centre for Biomedical Research, The Queen's Medical Centre, University of Hawaii Cancer Centre and John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fleig
authors.affiliation: Centre for Biomedical Research, The Queen's Medical Centre, University of Hawaii Cancer Centre and John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
authors.forename: Reinhold
authors.identifier: 0000-0002-5366-1537
authors.initials: R
authors.lastname: Penner
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology*; D045744:Cell Line, Tumor; D002645:Chickens; D057809:HEK293 Cells; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D051381:Rats; D000071737:Stromal Interaction Molecule 1 / Q000502:physiology; D000071738:Stromal Interaction Molecule 2 / Q000502:physiology; D050053:TRPM Cation Channels / Q000235:genetics / Q000502:physiology*
chemical_list: D015220:Calcium Channels; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D050053:TRPM Cation Channels; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D002118:Calcium
keywords: SOCE; TRPM7; αKinase