Different shapes of the steroid hormone 1α,25(OH) 2-vitamin D 3 act as agonists for two different receptors in the vitamin D endocrine system to mediate genomic and rapid responses☆

Abstract

Vitamin D 3 produces biologic responses as a consequence of its metabolism into 1α,25(OH) 2-vitamin D 3 [1α,25(OH) 2D 3] and 24R,25(OH) 2-vitamin D 3. The metabolic production of these two seco steroids and their generation of the plethora of biologic actions that are attributable to the parent vitamin D 3 are orchestrated via the integrated operation of the vitamin D endocrine system. This system is very similar in its organization to that of classic endocrine systems and is characterized by an endocrine gland (the kidney, the source of the two steroid hormones), target cells which possess receptors for the steroid hormones, and a feed-back loop involving changes in serum Ca 2+ that alter the secretion of parathyroid hormone (a stimulator of the renal 1-hydroxylase) which modulates the output by the kidney of the steroid hormones. There are, however, at least two unique aspects to the vitamin D endocrine system. (a) The chemical structures of vitamin D and its steroid hormones dictate that these be highly conformationally flexible molecules present a wide variety of shapes to their biologic environments. (b) It is now believed that 1α,25(OH) 2D 3 produces biologic responses through two distinct receptors which recognize totally different shapes of the conformationally flexible 1α,25(OH) 2D 3. Thus, the classic actions of 1α,25(OH) 2D 3 to regulate gene transcription occur as a consequence of the stereospecific interaction of a modified 6-s- trans bowl-shape of 1α,25(OH) 2D 3 with its nuclear receptor (VDR nuc). The ability of 1α,25(OH) 2D 3 to generate a variety of rapid (seconds to minutes) biologic responses (opening of chloride channels, activation of PKC and MAP kinases) requires a planar 6-s- cis ligand shape which is recognized by a putative plasma membrane receptor (VDR mem) to initiate appropriate signal transduction pathways. This report summarizes the evidence for the specificity of different ligand shapes and the operation of the two receptor families for 1α,25(OH) 2D 3.