UC San Diego

The endoplasmic reticulum (ER) is a highly tortuous organelle that spans throughout a cell with a continuous membrane containing ion channels, pumps, and transporters. It is unknown if stimuli that gate ER ion channels can trigger substantial membrane potential fluctuations and if those fluctuations spread beyond their site of origin. Here, we visualize ER membrane potential dynamics in cultured rat hippocampal neurons by targeting a genetically-encoded voltage indicator specifically to the ER. We report a polarized ER membrane potential that bidirectionally responds to synaptic activity over hundreds of milliseconds. Direct stimulation of ER ion channels generates depolarizations that scale with stimulus strength and reach tens of millivolts in amplitude. However, ER potentials do not spread beyond the site of receptor activation, exhibiting steep attenuation that is exacerbated by BK channels. Thus, segments of ER can generate large depolarizations that are actively restricted from impacting nearby, contiguous regions of membrane.