, 2006) In our study, we found that elevated mTOR signaling in P

, 2006). In our study, we found that elevated mTOR signaling in POMC neurons increased KATP current, and this heightened KATP channel activity silenced POMC neurons and reduced leptin-stimulated α-MSH secretion; Pomc-cre;Tsc1-f/f mice also exhibited a hyperphagic obese phenotype ( Figures 4 and 5). Selleckchem Rapamycin Since increasing PIP3 level on the plasma membrane activates PI3K, a canonical activator of mTOR ( Wullschleger et al., 2006), it is expected that deleting PTEN in POMC neurons may also activate mTOR, and this elevated mTOR activity could activate KATP channels, as we have shown in our study. Whereas deleting PTEN increases plasma PIP3 thereby prolonging

the opening time of KATP channels ( Plum et al., 2006), the elevated mTOR signaling in POMC neurons lacking TSC1 likely causes an ATM/ATR inhibitor increase in KATP channel density, because the maximum KATP current level is doubled in the presence of diazoxide ( Figure 4I). Since PIP3 and diazoxide

share the same common mechanism for KATP channel activation due to increased open time ( Koster et al., 1999), the maximum KATP current in POMC neurons without TSC1 should remain unchanged if activating mTOR were to increase KATP current by generating PIP3. It is of interest to note that deleting PTEN in POMC neurons also results in hypertrophic soma as in POMC neurons with an elevated mTOR activity ( Mori et al., 2009). It thus seems likely that activation of the PI3K pathway will have effects similar to those caused by elevating mTOR activity, likely an increase of KATP channel density, in addition to an increase of channel open time due to an increase of phosphoinositides old such as PIP3. Rapamycin has been found to affect the expression of Kv1.1 and Kv4.2 in dendrites of hippocampal

neurons (Lee et al., 2011; Raab-Graham et al., 2006). Here we provide another example of how mTOR regulates neuronal activity by controlling ion channel density. Under physiological conditions, the ion channel density in neurons is tightly regulated (Ma and Jan, 2002). For example, when Parton et al. (2007) expressed in transgenic mice a mutant form of Kir6.2 under the POMC promoter, POMC neurons in these transgenic mice nonetheless exhibit normal levels of KATP channel density (Parton et al., 2007). Ion channel density may be controlled at several different levels including transcription, translation, trafficking, and quality control of the endoplasmic reticulum (ER) (Ma et al., 2001). We found that POMC neurons from old mice express the transcripts for KATP channel subunits Kir6.2 and SUR1, for the most common KATP channel composition in neurons (van den Top et al., 2007). As functional KATP requires the coassembly of Kir6.2 and SUR1 (Schwappach et al.

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