Introduction

Calcium is one of the most important second messenger molecules used by living cells. Signalling carried out by calcium ions plays an important role in many cellular processes and because of its universal nature, disruption of calcium homeostasis under pathological conditions can have numerous consequences.

Due to its importance, calcium homeostasis is a tightly regulated event and many molecules and subcellular structures are involved in maintaining its optimal levels and pathways. Calcium enters the cell from extracellular space through plasma membrane, and once within the cell its levels are regulated by various intercellular stores, pumps, and buffer proteins. One way of entry into the cell is through voltage-gated calcium channels (VGCC) on cellular plasma membrane. Calcium entry through VGCC is an important physiolgical event, and proper functioning of these channels is crucial in many cellular processes. VGCC are expressed in many diverse cells of the human body and their pharmacological properties are independent of the cell type where they reside.

L-type calcium channels (LTCC) are voltage-gated calcium channels that are ubiquitously expressed in the cells of the central nervous system (CNS), the immune system and the gastrointestinal tract, amongst others. During development LTCC are highly expressed in the brain, and their optimal functioning is of central importance in many aspects of embryonic and postnatal brain development, including neuronal gene expression and differentiation, growth, branching, migration, and structural organisation of developing neurons. Calcium influx through these channels is directly involved in secretion of neurotransmitters and hormones, and plays a pivotal role in development of motor coordination and sensory processing. Furthermore, calcium signalling is the molecular mechanism of integration of neural circuits in the CNS, and is able to directly moderate electrical activity and excitability.

Maintenance of calcium homeostasis is of crucial importance in the proper functioning of the immune system and inflammatory responses, such as responsiveness of T and B lymphocytes, differentiation of T helper cells into Th1 and Th2 subsets and secretion of proinflammatory cytokines. Activities of LTCC and elevations in intracellular calcium level are the central element in the activation of brain immune cells.

LTCC are also expressed in endothelial and smooth muscle cells that line blood vessels, where their activities are closely involved cerebral blood flow and maintenance of blood brain barrier, especially in the developing brain. The same is true of the cells lining the gastrointestinal tract, in which LTCC and cellular levels of calcium play an important role in gut inflammation and permeability, gut motility and gastric acid secretion. In addition, LTCC are expressed in pancreatic beta cells, where their activities govern many aspects of pancreatic function, including digestive enzymes and insulin production and secretion.

Calcium influx through LTCC plays a crucial role in mitochondrial calcium overload and downstream mitochondrial and cellular dysfuctions, and elevation of intracellular calcium level is responsible for activation of ROS-generating enzymes and formation of free radicals by the mitochondria.

Timothy syndrome is a multisystem disorder in which a mutation in a gene that encodes Ca(V)1.2 L-type calcium channel leads to loss of channel inactivation and subsequent intracellular calcium overload in various cell types. Such disturbances in calcium homoestasis are thought to underlie the multiorgan dysfunction observed in this disorder, which includes congenital heart disease, immune deficiency, irregular sleep patterns, hypoglycemia, cognitive abnormalities, and autism [15454078].

Autism, or Autism Spectrum Disorders (ASD), is a group of neurodevelopmental disorders that manifest at an early age and is characterised by impairments in social interaction, communication, interests, imagination and activities. Apart from neurobehavioural symptoms, ASD individuals frequently present with impairments in areas such as motor function and coordination, sensitivities and abnormalities in visual and auditory processing, various gastrointestinal symptoms, and immune dysfunction. As autism is a highly heterogenous disorder, the symptoms can vary greatly in each affected individual.

Numerous findings in recent years point to underlying biological abnormalities in autism, including irregularities in neurotransmitter systems, cholesterol metabolism, mitochondrial enzyme activities, and levels and secretion rhythms of hormones; decreased cerebral blood flow and increased cerebral water content; elevated markers of oxidative stress; altered intestinal microflora; and intestinal damage and inflammation. In addition to the active, ongoing inflammation in the gastrointestinal tract and the CNS in autism, results of numerous studies point to an abnormality of the immune function such as the absence of adaptive immune system/T cell activation following stimulation, decreased NK cells activity, dysregulated apoptosis mechanisms, imbalances of serum immunoglobulin levels, increased numbers of monocytes, and abnormal T helper cell ratio.

It has been suggested in the past that disturbances in calcium signalling pathways may be the underlying molecular cause of autism [17275285]. Furthermore, a recent postmortem study revealed significantly elevated calcium levels in autistic brains compared to controls, followed by elevations of mitochondrial aspartate/glutamate carrier rates and mitochondrial metabolism and oxidation rates (18607376).

This paper further explores the potential role of dysfunctional calcium homeostasis, and in particular the functional disturbances of voltage gated calcium channels, that could lead to pathologies of autism. Various factors that are capable of disturbing the functioning of VGCC in critical stages of human development are discussed. Particular attention is given to the role of chemokine receptors as modulators of calcium signalling and possible implications of these events in etiology of autism.

In addition, the different ways in which sex hormones influence functioning of VGCC are proposed to be the reason for greater prevalence of autism in males than females.