Vitamin D deficiency: infertility and neurodevelopmental diseases (attention deficit hyperactivity disorder, autism, and schizophrenia).

The process of development depends on a number of signaling systems that regulates the progressive sequence of developmental events. Infertility and neurodevelopmental diseases, such as attention deficit hyperactivity disorder, autism spectrum disorders, and schizophrenia, are caused by specific alterations in these signaling processes. Calcium signaling plays a prominent role throughout development beginning at fertilization and continuing through early development, implantation, and organ differentiation such as heart and brain development. Vitamin D plays a major role in regulating these signaling processes that control development. There is an increase in infertility and an onset of neurodevelopmental diseases when vitamin D is deficient. The way in which vitamin D deficiency acts to alter development is a major feature of this review. One of the primary functions of vitamin D is to maintain the phenotypic stability of both the Ca2+ and redox signaling pathways that play such a key role throughout development.

Vitamin D deficiency accelerates ageing and age-related diseases: a novel hypothesis.

Ageing can occur at different rates, but what controls this variable rate is unknown. Here I have developed a hypothesis that vitamin D may act to control the rate of ageing. The basis of this hypothesis emerged from studyng the various cellular processes that control ageing. These processes such as autophagy, mitochondrial dysfunction, inflammation, oxidative stress, epigenetic changes, DNA disorders and alterations in Ca2+ and reactive oxygen species (ROS) signalling are all known to be regulated by vitamin D. The activity of these processes will be enhanced in individuals that are deficient in vitamin D. Not only will this increase the rate of ageing, but it will also increase the probability of developing age-related diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and cardiovascular disease. In individual with normal vitamin D levels, these ageing-related processes will occur at lower rates resulting in a reduced rate of ageing and enhanced protection against these age-related diseases.

Vitamin D deficiency and diabetes.

Vitamin D deficiency has been linked to the onset of diabetes. This review summarizes the role of Vitamin D in maintaining the normal release of insulin by the pancreatic beta cells (ß-cells). Diabetes is initiated by the onset of insulin resistance. The ß-cells can overcome this resistance by releasing more insulin, thus preventing hyperglycaemia. However, as this hyperactivity increases, the ß-cells experience excessive Ca2+ and reactive oxygen species (ROS) signalling that results in cell death and the onset of diabetes. Vitamin D deficiency contributes to both the initial insulin resistance and the subsequent onset of diabetes caused by ß-cell death. Vitamin D acts to reduce inflammation, which is a major process in inducing insulin resistance. Vitamin D maintains the normal resting levels of both Ca2+ and ROS that are elevated in the ß-cells during diabetes. Vitamin D also has a very significant role in maintaining the epigenome. Epigenetic alterations are a feature of diabetes by which many diabetes-related genes are inactivated by hypermethylation. Vitamin D acts to prevent such hypermethylation by increasing the expression of the DNA demethylases that prevent hypermethylation of multiple gene promoter regions of many diabetes-related genes. What is remarkable is just how many cellular processes are maintained by Vitamin D. When Vitamin D is deficient, many of these processes begin to decline and this sets the stage for the onset of diseases such as diabetes.

Vitamin D and Depression: Cellular and Regulatory Mechanisms.

Depression is caused by a change in neural activity resulting from an increase in glutamate that drives excitatory neurons and may be responsible for the decline in the activity and number of the GABAergic inhibitory neurons. This imbalance between the excitatory and inhibitory neurons may contribute to the onset of depression. At the cellular level there is an increase in the concentration of intracellular Ca2+ within the inhibitory neurons that is driven by an increase in entry through the NMDA receptors (NMDARs) and through activation of the phosphoinositide signaling pathway that generates inositol trisphosphate (InsP3) that releases Ca2+ from the internal stores. The importance of these two pathways in driving the elevation of Ca2+ is supported by the fact that depression can be alleviated by ketamine that inhibits the NMDARs and scopolamine that inhibits the M1 receptors that drive InsP3/Ca2+ pathway. This increase in Ca2+ not only contributes to depression but it may also explain why individuals with depression have a strong likelihood of developing Alzheimer's disease. The enhanced levels of Ca2+ may stimulate the formation of Aß to initiate the onset and progression of Alzheimer's disease. Just how vitamin D acts to reduce depression is unclear. The phenotypic stability hypothesis argues that vitamin D acts by reducing the increased neuronal levels of Ca2+ that are driving depression. This action of vitamin D depends on its function to maintain the expression of the Ca2+ pumps and buffers that reduce Ca2+ levels, which may explain how it acts to reduce the onset of depression.

Lymphocyte Activation in Health and Disease.

Lymphocytes employ a complex assembly of signaling elements that have been organized on a spatiotemporal map to define their role in stimulating both proliferation and apoptosis. The antigen/major histocompatibility complex (MHC) initiates the sequence by organizing the assembly of an active T-cell receptor (TCR) complex responsible for transmitting information down various signaling cassettes (e.g., the IP3/Ca2+, DAG/ PKC, ras/MAPK, and the PI 3-K pathways). It is proposed that CD28 may exert its costimulatory action by facilitating the assembly of an effective scaffold of signaling elements within the TCR complex. The absence of costimulation through CD28 seems to result in the assembly of a defective scaffold that reverses slowly and may thus account for the state of unresponsiveness responsible for peripheral T-cell tolerance. The signaling cassettes activated by the TCR and CD28 then engage cytosolic factors that transmit information into the nucleus to activate the genes that code for the IL-2 and Fas signaling pathways. The IL-2 and Fas receptors employ additional signaling cassettes (e.g., the JAK/STAT and the sphingomyelinase/ceramide pathways) to mediate their effects on proliferation and apoptosis, respectively. Information concerning these signaling systems is beginning to provide therapeutic strategies to manipulate the immune system to overcome human immunodeficiency virus (HIV) infection, autoimmune diseases, and graft rejection.

The Inositol Trisphosphate/Calcium Signaling Pathway in Health and Disease.

Many cellular functions are regulated by calcium (Ca(2+)) signals that are generated by different signaling pathways. One of these is the inositol 1,4,5-trisphosphate/calcium (InsP3/Ca(2+)) signaling pathway that operates through either primary or modulatory mechanisms. In its primary role, it generates the Ca(2+) that acts directly to control processes such as metabolism, secretion, fertilization, proliferation, and smooth muscle contraction. Its modulatory role occurs in excitable cells where it modulates the primary Ca(2+) signal generated by the entry of Ca(2+) through voltage-operated channels that releases Ca(2+) from ryanodine receptors (RYRs) on the internal stores. In carrying out this modulatory role, the InsP3/Ca(2+) signaling pathway induces subtle changes in the generation and function of the voltage-dependent primary Ca(2+) signal. Changes in the nature of both the primary and modulatory roles of InsP3/Ca(2+) signaling are a contributory factor responsible for the onset of a large number human diseases.

Vitamin D, reactive oxygen species and calcium signalling in ageing and disease.

Vitamin D is a hormone that maintains healthy cells. It functions by regulating the low resting levels of cell signalling components such as Ca(2+) and reactive oxygen species (ROS). Its role in maintaining phenotypic stability of these signalling pathways depends on the ability of vitamin D to control the expression of those components that act to reduce the levels of both Ca(2+) and ROS. This regulatory role of vitamin D is supported by both Klotho and Nrf2. A decline in the vitamin D/Klotho/Nrf2 regulatory network may enhance the ageing process, and this is well illustrated by the age-related decline in cognition in rats that can be reversed by administering vitamin D. A deficiency in vitamin D has also been linked to two of the major diseases in man: heart disease and Alzheimer's disease (AD). In cardiac cells, this deficiency alters the Ca(2+) transients to activate the gene transcriptional events leading to cardiac hypertrophy and the failing heart. In the case of AD, it is argued that vitamin D deficiency results in the Ca(2+) landscape that initiates amyloid formation, which then elevates the resting level of Ca(2+) to drive the memory loss that progresses to neuronal cell death and dementia.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'.

Vitamin D: a custodian of cell signalling stability in health and disease.

There is increasing evidence that a deficiency in vitamin D contributes to many human diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), hypertension and cardiovascular disease. The ability of vitamin D to maintain healthy cells seems to depend on its role as a guardian of phenotypic stability particularly with regard to the reactive oxygen species (ROS) and Ca2+ signalling systems. Vitamin D maintains the expression of those signalling components responsible for stabilizing the low-resting state of these two signalling pathways. This vitamin D signalling stability hypothesis proposes that vitamin D, working in conjunction with klotho and Nrf2 (nuclear factor-erythroid-2-related factor 2), acts as a custodian to maintain the normal function of the ROS and Ca2+ signalling pathways. A decline in vitamin D levels will lead to an erosion of this signalling stability 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.

Vitamin D cell signalling in health and disease.

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 Ca(2+) 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 Ca(2+) 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 Ca(2+) signalling.

Calcium signalling and psychiatric disease: bipolar disorder and schizophrenia.

Neurons have highly developed Ca(2+) signalling systems responsible for regulating many neural functions such as the generation of brain rhythms, information processing and the changes in synaptic plasticity that underpins learning and memory. The signalling mechanisms that regulate neuronal excitability are particularly important for processes such as sensory perception, cognition and consciousness. The Ca(2+) signalling pathway is a key component of the mechanisms responsible for regulating neuronal excitability, information processing and cognition. Alterations in gene transcription are particularly important as they result in subtle alterations in the neuronal signalling mechanisms that have been implicated in many neural diseases. In particular, dysregulation of the Ca(2+) signalling pathway has been implicated in the development of some of the major psychiatric diseases such as bipolar disorder (BPD) and schizophrenia.

Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival.

Bcl-2 interacts with the inositol 1,4,5-trisphosphate receptor (InsP3R) and thus prevents InsP3-induced Ca(2+) elevation that induces apoptosis. Here we report that Bcl-2 binds dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a protein kinase A (PKA)-activated and calcineurin (CaN)-deactivated inhibitor of protein phosphatase 1 (PP1). Bcl-2 docks DARPP-32 and CaN in a complex on the InsP3R, creating a negative feedback loop that prevents exaggerated Ca(2+) release by decreasing PKA-mediated InsP3R phosphorylation. T-cell activation increases PKA activity, phosphorylating both the InsP3R and DARPP-32. Phosphorylated DARPP-32 inhibits PP1, enhancing InsP3R phosphorylation and Ca(2+) release. Elevated Ca(2+) activates CaN, which dephosphorylates DARPP-32 to dampen Ca(2+) release by eliminating PP1 inhibition to enable it to dephosphorylate the InsP3R. Knocking down either Bcl-2 or DARPP-32 abrogates this feedback mechanism, resulting in increased Ca(2+) elevation and apoptosis. This feedback mechanism appears to be exploited by high levels of Bcl-2 in chronic lymphocytic leukemia cells, repressing B-cell receptor-induced Ca(2+) elevation and apoptosis.

Calcium regulation of neural rhythms, memory and Alzheimer's disease.

Alzheimer's disease (AD) begins with a decline in cognition followed by neuronal cell death and dementia. These changes have been linked to a deregulation of Ca(2+) signalling caused by a progressive increase in the resting level of Ca(2+), which may influence cognition by interfering with the rhythm rheostat that controls the sleep/wake cycle. The rise in resting levels of Ca(2+) may not alter the processes of memory acquisition during consciousness (gamma and theta rhythms), but may duplicate some of the events that occur during the slow oscillations responsible for the twin processes of memory consolidation and memory erasure that occur during sleep. The persistent elevation in the resting level of Ca(2+) induced by an accumulation of amyloid ß (Aß) oligomers duplicates a similar small global elevation normally restricted to the period of slow oscillations when memories are erased during sleep. In AD, such a rapid erasure of memories soon after they are acquired during the wake period means that they are not retained for consolidation during sleep. The Aß deregulates Ca(2+) signalling through direct effects on the neurons and indirectly by inducing inflammatory responses in the microglia and astrocytes. Some of these deleterious effects of Aß may be alleviated by vitamin D.

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia.

Neurons have highly developed Ca(2+) signaling systems responsible for regulating a large number of neural functions such as the control of brain rhythms, information processing and the changes in synaptic plasticity that underpin learning and memory. The tonic excitatory drive, which is activated by the ascending arousal system, is particularly important for processes such as sensory perception, cognition and consciousness. The Ca(2+) signaling pathway is a key component of this arousal system that regulates the neuronal excitability responsible for controlling the neural brain rhythms required for information processing and cognition. Dysregulation of the Ca(2+) signaling pathway responsible for many of these neuronal processes has been implicated in the development of some of the major neural diseases in man such as Alzheimer disease, bipolar disorder and schizophrenia. Various treatments, which are known to act by reducing the activity of Ca(2+) signaling, have proved successful in alleviating the symptoms of some of these neural diseases.

Calcium signalling remodelling and disease.

A wide range of Ca2+ signalling systems deliver the spatial and temporal Ca2+ signals necessary to control the specific functions of different cell types. Release of Ca2+ by InsP3 (inositol 1,4,5-trisphosphate) plays a central role in many of these signalling systems. Ongoing transcriptional processes maintain the integrity and stability of these cell-specific signalling systems. However, these homoeostatic systems are highly plastic and can undergo a process of phenotypic remodelling, resulting in the Ca2+ signals being set either too high or too low. Such subtle dysregulation of Ca2+ signals have been linked to some of the major diseases in humans such as cardiac disease, schizophrenia, bipolar disorder and Alzheimer's disease.

Calcium signalling and Alzheimer's disease.

New insights into how Ca(2+) regulates learning and memory have begun to provide clues as to how the amyloid-dependent remodelling of neuronal Ca(2+) signalling pathways can disrupt the mechanisms of learning and memory in Alzheimer's disease (AD). The calcium hypothesis of AD proposes that activation of the amyloidogenic pathway remodels the neuronal Ca(2+) signalling pathways responsible for cognition by enhancing the entry of Ca(2+) and/or the release of internal Ca(2+) by ryanodine receptors or InsP(3) receptors. The specific proposal is that Ca(2+) signalling remodelling results in a persistent elevation in the level of Ca(2+) that constantly erases newly acquired memories by enhancing the mechanism of long-term depression (LTD). Neurons can still form memories through the process of LTP, but this stored information is rapidly removed by the persistent activation of LTD. Further dysregulation in Ca(2+) signalling will then go on to induce the neurodegeneration that characterizes the later stages of dementia.

Calcium hypothesis of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused by an increase in amyloid metabolism. The calcium hypothesis of AD explores how activation of the amyloidogenic pathway may function to remodel the neuronal Ca(2+) signaling pathways responsible for cognition. Hydrolysis of the beta-amyloid precursor protein (APP) yields two products that can influence Ca(2+) signaling. Firstly, the amyloids released to the outside form oligomers that enhance the entry of Ca(2+) that is pumped into the endoplasmic reticulum (ER). An increase in the luminal level of Ca(2+) within the ER enhances the sensitivity of the ryanodine receptors (RYRs) to increase the amount of Ca(2+) being released from the internal stores. Secondly, the APP intracellular domain may alter the expression of key signaling components such as the RYR. It is proposed that this remodeling of Ca(2+) signaling will result in the learning and memory deficits that occur early during the onset of AD. In particular, the Ca(2+) signaling remodeling may erase newly acquired memories by enhancing the mechanism of long-term depression that depends on activation of the Ca(2+)-dependent protein phosphatase calcineurin. The alteration in Ca(2+) signaling will also contribute to the neurodegeneration that characterizes the later stages of dementia.

Inositol trisphosphate and calcium signalling mechanisms.

Studies on control of fluid secretion by an insect salivary gland led to the discovery of inositol trisphosphate (IP3) and its role in calcium signalling. Many cell stimuli act on receptors that are coupled to phospholipase C that hydrolyses phosphatidylinosol 4,5-bisphosphate (PIP2) to release IP3 to the cytosol. IP3 receptors located on the endoplasmic reticulum respond to this elevation of IP3 by releasing Ca2+, which is often organized into characteristic spatial (elementary events and waves) and temporal (Ca2+ oscillations) patterns. This IP3/Ca2+ pathway is a remarkably versatile signalling system that has been adapted to control processes as diverse as fertilization, proliferation, contraction, cell metabolism, vesicle and fluid secretion and information processing in neuronal cells.

Smooth muscle cell calcium activation mechanisms.

Smooth muscle cell (SMC) contraction is controlled by the Ca2+ and Rho kinase signalling pathways. While the SMC Rho kinase system seems to be reasonably constant, there is enormous variation with regard to the mechanisms responsible for generating Ca2+ signals. One way of dealing with this diversity is to consider how this system has been adapted to control different SMC functions. Phasic SMCs (vas deferens, uterus and bladder) rely on membrane depolarization to drive Ca2+ influx across the plasma membrane. This depolarization can be induced by neurotransmitters or through the operation of a membrane oscillator. Many tonic SMCs (vascular, airway and corpus cavernosum) are driven by a cytosolic Ca2+ oscillator that generates periodic pulses of Ca2+. A similar oscillator is present in pacemaker cells such as the interstitial cells of Cajal (ICCs) and atypical SMCs that control other tonic SMCs (gastrointestinal, urethra, ureter). The changes in membrane potential induced by these cytosolic oscillators does not drive contraction directly but it functions to couple together individual oscillators to provide the synchronization that is a characteristic feature of many tonic SMCs.

Inositol trisphosphate and calcium oscillations.

InsP3 has two important functions in generating Ca2+ oscillations. It releases Ca2+ from the internal store and it can contribute to Ca2+ entry. A hypothesis has been developed to describe a mechanism for Ca2+ oscillations with particular emphasis on the way agonist concentration regulates oscillator frequency. The main idea is that the InsP3 receptors are sensitized to release Ca2+ periodically by cyclical fluctuations of Ca2+ within the lumen of the endoplasmic reticulum. Each time a pulse of Ca2+ is released, the luminal level of Ca2+ declines and has to be replenished before the InsP3 receptors are resensitized to deliver the next pulse of Ca2+. It is this loading of the internal store that explains why frequency is sensitive to external Ca2+ and may also account for how variations in agonist concentration are translated into changes in oscillation frequency. Variations in agonist-induced entry of external Ca2+, which can occur through different mechanisms, determine the variable rates of store loading responsible for adjusting the sensitivity of the InsP3 receptors to produce the periodic pulses of Ca2+. The Ca2+ oscillator is an effective analogue-to-digital converter in that variations in the concentration of the external stimulus are translated into a change in oscillator frequency.