The Ras-like GTPase Rem2 is a potent endogenous inhibitor of calcium/calmodulin-dependent kinase II activity

Abstract

CaMKII is a well-characterized, abundant protein kinase that regulates a diverse set of functions in a tissue specific manner. For example, in heart muscle, CaMKII regulates Ca2+ homeostasis while in neurons CaMKII regulates activity-dependent dendritic remodeling and Long Term Potentiation (LTP), a biological correlate of learning and memory. Previously, we identified the noncanonical GTPase Rem2 as a critical regulator of dendrite branching and synapse formation in the vertebrate nervous system. Here, we report that Rem2 directly interacts with CaMKII and potently inhibits the activity of the intact holoenzyme, a previously undescribed function for the Rem2 protein. To date, only one other endogenous inhibitor of CaMKII has been described: CaMKIIN, which blocks CaMKII activity through binding to the catalytic domain. Our data suggest that Rem2 inhibits CaMKII through a novel mechanism, as inhibition requires the presence of the association domain of CaMKII. Our biochemical finding that Rem2 is a direct, endogenous inhibitor of CaMKII activity, coupled with known functions of Rem2 in neurons, provides a framework which will enable future experiments probing the physiological role of CaMKII inhibition in a cellular context.

Rem2 signaling affects neuronal structure and function in part by regulation of gene expression

“…5). Therefore, we favor a model where Rem2 functions as a cytosolic signaling molecule to mediate changes in gene expression in the nucleus, perhaps by interacting with the CaMK signaling pathways [14, 64]. …”

Rem2 stabilizes intrinsic excitability and spontaneous firing in visual circuits

“…Rem2 is a noncanonical Ras-like GTPase, expressed throughout the cell ( Ghiretti and Paradis, 2011 ) and is unlikely to be regulated by its nucleotide binding state ( Correll et al, 2008 ) in contrast to canonical Ras family members. The mechanism by which Rem2 transduces signals is an open area of investigation, although it has been shown to associate with VGCC subunits ( Chen et al, 2005 ; Finlin et al, 2006 ; Finlin et al, 2005 ; Pang et al, 2010 ) and CaMKII ( Flynn et al, 2012 ; Royer et al, 2017 ). In addition, our previous studies demonstrated that Rem2 functions in a CaMK signaling pathway to regulate dendritic complexity ( Ghiretti et al, 2014 ).…”

“…We found that the expression of a number of ion channels, important for establishing neuronal excitability, are regulated by Rem2 signaling in an activity-dependent manner ( Kenny et al, 2017 ). We also recently demonstrated that Rem2 is a novel inhibitor of CaMKII catalytic activity ( Royer et al, 2017 ). Interestingly, CaMKII has been shown to modulate calcium channel function to alter intrinsic excitability ( Sahu et al, 2017 ; van Welie et al, 2011 ).…”