Nonnuclear effects of the steroid hormone 1 alpha,25(OH)2-vitamin D3: analogs are able to functionally differentiate between nuclear and membrane receptors.

The steroid hormone 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] stimulates biological responses via both genomic mechanisms and nongenomic mechanisms (opening of voltage-gated Ca2+ channels). We report here that the two closed B-ring steroid analogs of 1 alpha,25(OH)2D3, 1 alpha,25(OH)2-7-dehydrocholesterol and 1 alpha,25(OH)2-lumisterol3, are able to generate the nongenomic response, transcaltachia, without the ability to compete with the natural metabolite for binding to its nuclear receptor. We propose that the nongenomic membrane associated receptor can accept the ligand in its closed "6-s-cis" conformation whereas the nuclear receptor prefers the extended "6-s-trans" conformer.