Vitamin D cell signalling in health and disease

• Vitamin D deficiency causes many human diseases.
• A phenotypic stability hypothesis explains how Vitamin D maintains cellular functions.
• Vitamin D maintains the redox and Ca2+ signalling systems.
• Vitamin D increases expression of Nrf2 and Klotho that also control Ca2+ and redox signalling.
• Many major diseases are caused by a decline in the Vitamin D/klotho/Nrf2 regulatory network.

Vitamin D deficiency has been linked to many human diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), hypertension and cardiovascular disease. A Vitamin D phenotypic stability hypothesis, which is developed in this review, attempts to describe how this vital hormone acts to maintain healthy cellular functions. This role of Vitamin D as a guardian of phenotypic stability seems to depend on its ability to maintain the redox and Ca2+ signalling systems. It is argued that its primary action is to maintain the expression of those signalling components responsible for stabilizing the low resting state of these two signalling pathways. This phenotypic stability role is facilitated through the ability of vitamin D to increase the expression of both Nrf2 and the anti-ageing protein Klotho, which are also major regulators of Ca2+ and redox signalling. A decline in Vitamin D levels will lead to a decline in the stability of this regulatory signalling network and may account for why so many of the major diseases in man, which have been linked to vitamin D deficiency, are associated with a dysregulation in both ROS and Ca2+ signalling.