What is Calcium Signaling?

By Sarah MooreReviewed by Michael Greenwood, M.Sc.

Calcium is fundamental to almost all human life processes, from fertilization to secretion, neurotransmission, and cell migration.

Image Credit: Juan Gaertner/Shutterstock.com

It is vital to the regulation of cell activities through its role as a second messenger. Calcium signaling is the process whereby low cytoplasmic concentrations are deliberately increased to activate specific, necessary events required by the cell. This may be excitability, exocytosis, motility, apoptosis, or transcription.

We discuss the pathway that mediates calcium signaling, the processes that it influences, and the role of calcium signaling in disease.

Phospholipase C signaling and calcium influx

Almost every cell type and bodily tissue use calcium ion (Ca²⁺) signaling to carry out a vital process. This process occurs similarly across cells. It begins with a low concentration of calcium ions (Ca²⁺) in the cell cytoplasm, which is then forcibly increased to trigger intended downstream events.

While several pathways can govern the generation of Ca²⁺ signals, the phospholipase C pathway is possibly the most common. Through this mechanism, the lipid metabolizing enzyme, phospholipase C (PLC), is activated by any of several cell surface receptors, commonly G protein-coupled receptors or receptor tyrosine kinases.

The activated PLX then hydrolyzes PIP2, the membrane phospholipid, creating two-second messengers in the form of IP3 and diacylglycerol (DAG). DAG then attaches protein kinase C (PKC) to the plasma membrane, and IP3 acts as a channel for Ca²⁺, releasing it from the endoplasmic reticulum. The released Ca²⁺ then activates PKC by binding with it.

As a result, the decrease in Ca²⁺ levels within the endoplasmic reticulum causes Ca²⁺ to enter the cell through the activation of store-operated channels (SOCs). The opening of these channels causes an influx of calcium that is known as Ca²⁺release-activated Ca²⁺ current (ICRAC). Although much research has studied the ICRAC mechanism, scientists are still unclear on how exactly it works, although Orai1 and STIM1 have been implicated in moderating the process. Other studies have also suggested the roles of phospholipase A2 beta and nicotinic aside adenine dinucleotide phosphate (NAADP).

The influx of Ca²⁺ into the intracellular environment alters the membrane potential of the cell, which is key to maintaining numerous bodily functions, such as neuronal synaptic transmission or the depolarization of the heart.

Roles of calcium signaling

Calcium signaling is essential for the regulation of a diverse set of crucial functions within the human body, such as overseeing cell death, gene transcription, muscle contraction, exocytosis, neuronal transmission, cell motility (including the movement of flagella and cilia), fertilization, cell growth and proliferation, neurogenesis, synaptic plasticity, secretion of saliva, enzyme activity, and more.

Calcium is a ubiquitous intracellular messenger that can govern diverse cellular functions because it, directly and indirectly, modulates a myriad of different proteins that are involved in different jobs. Transcription factors such as NF-AT, kinases, and phosphatases, and calcium-binding protein calmodulin (CaM) are all impacted by calcium activity.

Calcium signaling and disease

Because calcium signaling is essential to the management of many vital processes, it is unsurprising that calcium signaling is implicated in the onset and maintenance of various diseases and illnesses, including neurodegenerative disorders such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD).

Research is generating a mounting body of evidence to support the idea that age-related dysregulation of neuronal Ca²⁺ homeostasis is linked with the pathogenesis of AD. It is considered that disrupted Ca²⁺ signaling has the potential to generate synaptic deficits, resulting in the accumulation of Aβ plaques and neurofibrillary tangles that are hallmarks of the disease.

Research is now investigating how small molecules specific to Ca²⁺ channels, handling proteins on the plasma membrane, and intracellular organelles membranes could be targeted to reverse neuronal Ca²⁺ dysregulation to treat AD.

What’s more, the last couple of decades have seen calcium signaling were identified as playing a key role in various cancers. Breast cancer, in particular, has become the main focus of this area of research.

The link between breast cancer and calcium signaling is due to the importance of the calcium ion in the generation of calcium in milk, which is vital to neonatal growth and development. Currently, many research projects are investigating the therapeutic potential of targeting abnormal Ca²⁺ signaling for several cancers.

Specifically, in breast cancer, multiple proteins (such as voltage-gated calcium channels, transient receptor potential channels, STIM and Orai proteins, ether-a-go-go potassium channels, calcium-activated potassium channels, calcium-activated chloride channels, muscarinic acetylcholine receptors) along with calcium signaling pathways are known to be altered or abnormal in breast cancer, and that these changes are related to the development and progression of the disease.

For this reason, calcium signaling is being explored as a pharmacological target.

Summary

Calcium ions are found in abundance all over the body, and their signaling is essential to many vital, life-supporting roles. It is most commonly governed by the phospholipase C pathway, which fosters the influx of calcium ions into the intracellular environment, having direct and indirect influences on many other proteins, triggering a variety of key processes.

Because of its key role in so many processes, calcium signaling has been linked to several diseases, and it is currently being explored as a therapeutic target for various illnesses, from Alzheimer's disease to breast cancer.