Figure 6.

A cellular model of STIM1 affecting mGluR1/5 activation of TRPC5 channels in POMC neurons. Store-operated calcium entry (SOCE) is a conserved mechanism by which the depletion of the endoplasmic reticulum (ER) calcium stores is conveyed to calcium-permeable channels at the plasma membrane, triggering calcium influx from the extracellular space and into the cell cytosol. A physiological mechanism responsible for the activation of SOCE results from the stimulation of G protein-coupled receptors associated with the IP3 and phospholipase C cascade, resulting in the release of calcium from ER, via the IP3 receptor (IP3R). Left panel, under physiological conditions, STIM1 interacts with TPRC5 channels thereby engaging these Ca²⁺ channels as store-operated channels, which are activated with ER depletion of Ca²⁺. Right Panel, however, under certain physiological conditions such as in females where estrogen downregulates the expression of STIM1, TRPC5 channels are converted to receptor-operated channels in POMC neurons. [In this study in males, we used CRISPR/SaCas9 mutagenesis of STIM1 to reduce its expression.] Therefore, glutamate binds to its receptor (mGluR1/5) to activate Gaq–PLCβ signaling cascade to facilitate TPRC5 channel opening, generating a robust inward Ca²⁺/Na⁺ current to depolarize POMC neurons to increase POMC neuronal excitability.