We have explored membrane-initiated estradiol signaling in several other systems, as well. For example, in dorsal root ganglion cells, ATP acts as a nociceptive messenger. In these cells, estradiol activates an ERα that is coupled to a metabotropic glutamate receptor that inhibits L-type voltage gated Ca2+ channels (VSCC) and attenuates the influx of calcium – thus, potentially attenuating painful signals. In a second system, the dopaminergic neurons of the substantia nigra, estradiol membrane signaling is mediated by another estrogen receptor, ERβ. Here, estradiol is neuroprotective and interacts with the IGF-1 system by activation of the phosphatidyl-inositol-3-kinase/Akt (PI3K/Akt) pathway. Estradiol acts both on neurons and through astrocytes to alter the ratio of anti-inflammatory to pro-inflammatory cytokines released may serve to protect against Parkinson’s disease.
