Abstract
The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) serves as a regulator of mRNA translation. Recent studies suggest that mTORC1 may also serve as a local, voltage sensor in the postsynaptic region of neurons. Considering biochemical, bioinformatics and imaging data, we hypothesize that the activity state of mTORC1 dynamically regulates local membrane potential by promoting and repressing protein synthesis of select mRNAs. Our hypothesis suggests that mTORC1 uses positive and negative feedback pathways, in a branch-specific manner, to maintain neuronal excitability within an optimal range. In some dendritic branches, mTORC1 activity oscillates between the “On” and “Off” states. We define this as negative feedback. In contrast, positive feedback is defined as the pathway that leads to a prolonged depolarized or hyperpolarized resting membrane potential, whereby mTORC1 activity is constitutively on or off, respectively. We propose that inactivation of mTORC1 increases the expression of voltage-gated potassium alpha (Kv1.1 and 1.2) and beta (Kvβ2) subunits, ensuring that the membrane resets to its resting membrane potential after experiencing increased synaptic activity. In turn, reduced mTORC1 activity increases the protein expression of syntaxin-1A and promotes the surface expression of the ionotropic glutamate receptor N-methyl-D-aspartate (NMDA)-type subunit 1 (GluN1) that facilitates increased calcium entry to turn mTORC1 back on. Under conditions such as learning and memory, mTORC1 activity is required to be high for longer periods of time. Thus, the arm of the pathway that promotes syntaxin-1A and Kv1 protein synthesis will be repressed. Moreover, dendritic branches that have low mTORC1 activity with increased Kv expression would balance dendrites with constitutively high mTORC1 activity, allowing for the neuron to maintain its overall activity level within an ideal operating range. Finally, such a model suggests that recruitment of more positive feedback dendritic branches within a neuron is likely to lead to neurodegenerative disorders.
Highlights
We have previously shown that stimulation of the ionotropic glutamate receptor N-methyl-D-aspartate (NMDA)-type (GluN or NMDAR) led to downstream activation of mechanistic target of rapamycin complex 1 (mTORC1) that can be blocked by (2 R)-amino-5-phosphonovaleric acid (AP5)—NMDAR antagonist—and rapamycin (Raab-Graham et al, 2006; Sosanya et al, 2013, 2015a)
We propose that the mTORC1-Off-dependent translation of Kv1.1 serves to ensure that the membrane resets to a normal resting potential, thereby maintaining neuronal excitability to be within an optimal operating range
We found that Cyclin-dependent kinase 5 (Cdk5) was differentially regulated in soluble and postsynaptic density (PSD) fractions (Table 1). mTORC1 inhibition increased Cdk5 protein expression in the soluble
Summary
The mammalian/mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase that is involved in many cellular processes (Hay and Sonenberg, 2004; Zoncu et al, 2011; Laplante and Sabatini, 2012). mTOR forms complexes with two distinct sets of proteins to give rise to mTORC1 and mTORC2, for complex 1 and 2 respectively. mTORC1 is well-characterized for. The dendrite-rich region of hippocampal CA1 stratum radiatum contains several mRNAs that code for ion channels, bringing to mind that other ion channel proteins, like Kv1.1, can be locally synthesized upon the right cues, (Table 1; Raab-Graham et al, 2006; Cajigas et al, 2012) The compartmentalization of these mRNAs, away from the soma or axons, suggests that their translation will only alter dendritic membrane properties in a site-specific manner. While the necessary elements (e.g., mRNAs, translation factors and location) to regulate dendritic membrane potential actively are readily available, it still remains unknown whether a general mechanism exists that can coordinate the expression of ion channels, receptors and their associated proteins to change the membrane potential dynamically. The proper surface expression of Kv1.1-containing channels depends on the co-assembly of Kv1.1 with other Kvα1-type mTORC1 Function in Postsynaptic Voltage-Sensing
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