Calcium Channels’ Role in Disease Development

Introduction

Voltage-gated calcium channels belong to a family of calcium channel proteins that are integrated in the membranes of both excitable and non-excitable cells. In many cells an influx of calcium triggers depolarization which can increase excitability. Calcium is a known intracellular messenger which not only plays a role in many signalling pathways but is also involved in neurotransmitter release and muscle contractions. Research emphasizes the role that voltage-gated calcium channels play in the development of many diseases, especially in humans. Changes in expression of various calcium channel genes can lead to pathophysiological changes that are common in a wide range of disorders. Channelopathies refer to diseases that arise from altered ion channel function or the proteins that regulate ion channels. Channelopathies specific to calcium channels can cause several disorders in humans including neurological, muscular, retinal, and cardiac disorders.

Hypothesis

This research focuses on the examination of diseases that develop as a result of channelopathies connected to calcium. The variety of diseases connected to this phenomenon is explained by Pancaroglu and Van Petegem (2018) as an outcome of different types of mutations in genes encoding the ion channels and their proteins. Calcium plays a vital role in regulating the functions of different structures in a human body since Ca2+ release-activated Ca2+ (CRAC) mechanism is associated with the functioning of the immune system, muscle fibers, and neural system. The main property of the machine is connected to the channel pore, which opens and allows calcium ions to migrate into a cell. This results in an increased concentration of calcium and triggers mechanisms such as cell migration, transcription of genes, and proliferation of cells. These encompass routine processes within a human body that allows its systems to function properly; however, in some cases, the calcium channels malfunction, affecting the mentioned processes. This paper hypothesizes that the improper functioning of the calcium channels leads to severe health impairments, including seizures and issues with the skeletal or cardiac muscles.

Understanding the primary mechanism that regulates the opening and closure of the calcium channels allows one to comprehend the effect that calcium has on the development of varied diseases, such as cardiovascular, neural, muscular, and renal conditions. For instance, the CRAC channels open and gate based on the movement that occurs within the channel pore (Pancaroglu & Van Petegem, 2018). The leaks that occur within the calcium channels affect the standard processes occurring in cells and lead to pathogenic mutations.

Therefore, the hypothesis of this research is that channelopathies of calcium channels can lead to the development of epilepsy, including absence epilepsy and muscular conditions and others. The work conducted by Zhang, Mori, Burgess, and Noebels (2002) addresses the connection between epilepsy seizures and channelopathies. Pancaroglu and Petegem (2018) present an in-depth overview of how calcium channel malfunctioning leads to subsequent issues with muscle fiber functioning. Therefore, this research will examine the properties of calcium channels and their impact on the neurological, muscular, and cardiovascular systems in regards to mutation and disease development.

Methods

In order to test the hypothesis regarding calcium channelopathies, one must examine the scholarly research n the topic, which focuses on the specific diseases and mechanisms of their development. For this paper, six articles were chosen, each pertaining to either neurological. This paper will present an examination of literature that focuses on calcium channelopathies and diseases caused by the malfunctioning of the ion channels. The examined literature used cryo-electron microscopy and other methodologies to evaluate the different stages of calcium channels and their impact on disease development.

One of the articles is a systemic review of clinical trials that focus on treatments of cardiovascular diseases that developed as a result of calcium channel mutations. This approach allows for understanding the potential for developing treatments that target calcium cells. Additioanlly, Zhang et al. (2002) based their research on the examination of mice brain slices to determine the impact of channel mutation on neural activity. The findings of each article are discussed and evaluated to summarize the primary findings and their importance for the scope of this paper. The questions that were answered in the examined literature relate to the specific impact that calcium has on the excitable cells and the possible channelopathies that result in diseases. More specifically, the literature focused on the mechanisms of signaling and other properties of calcium channels.

Literature Review

A very common neurological disorder that effects humans is known as idiopathic generalized epilepsies (IGE). Epilepsies are generally the result of hyperexcitable and hypersynchronous neurons which are caused by brain damage or genetics. Research on this disorder continuously implicates high and low voltage activated calcium channels as well as their ancillary subunits in IGE. Generalized epilepsies refer to seizure activity spanning both hemispheres on the brain and idiopathic seizures usually have a genetic component associated with it. An attribute of IGEs is the prevalence of absence seizures which are characterized by a sudden arrest of behaviour followed by impaired consciousness and termination before returning to normal behaviour.

EEG recordings have characterized absence seizures by spike and wave discharges which are a product of synchronous firing of thalamocortical networks. A strong link is observed between mutation effecting voltage gated calcium channels and the development of IGEs. Mutations in genes encoding T-type calcium channels, CACNA1G and CACNA1H, are common with IGE patients. Since epilepsies are a result of hyperactivity of neurons, mutations to the calcium channels involved are gain of function mutations which can shift activation thresholds and increase current density. Mutations of the T-type calcium channels are mostly located between the linker connecting the transmembrane segments S2 and S3. These mutations may not be enough to trigger epilepsy however, they may increase excitability in cells which in turn can contribute towards the generation of seizures.

Channelopathies are a term describing diseases caused by malfunction of the ion channel subunits. Pancaroglu and Petegem (2018) define ion channels as membrane proteins, and their primary function is ensuring the passage of ions across different membranes of a human body. Ion channels are responsible for shaping the action potential of neurons and aid signaling pathways. Channelopathies arise as a mutation of genes responsible for encoding this ion challenges, which leads to subsequent issues with ion passages. Therefore, ion challenges play a significant role in determining and enabling the functions of a human body, including muscles and neurons. In this context, it is essential to understand the main properties of ion channels – selectivity and gating capability (Pancaroglu & Petegem, 2018). The first element is connected to the ability of a specific channel to selections, while the second allows them to create a barrier. The difference in the electric currents across different ion channels is connected to their ability to open and close. Hence, ion channels are pathways with different properties and functions that allow sault ions, including calcium, to pass through cell membranes, and malfunction of these pathways is connected to a variety of pathophysiological diseases.

Ca2+ channels have an essential role in regulating the function of the muscular tissue. Calcium is regarded as an ” intracellular second messenger,” and the activity of these ion channels is connected to signaling pathways, which coordinate multi-cell activities (Pancaroglu & Petegem, 2018, p. 373). Voltage-gated calcium channels (CaVs) are a part of the plasma membrane, and their impairment affects the signaling properties of these channels. The examined article outlines the mechanism of calcium channels and the regulation of Ca+ release specific to muscle fibers.

Calcium Channels and Muscular Disorders

The Ryanodine Receptor (RYR) blocks the Ca2+ release from the sarcoplasmic reticulum (SR), therefore controlling the release of calcium from SR and endoplasmic reticulum (ER) (Pancaroglu & Petegem, 2018). Skeletal muscles of a human body contain RyR1, which are major ion channels that control the release of the calcium. Notably, the RyR2 is mostly found in cardiac myocytes, which explains the relationship between calcium channels and cardiovascular conditions.

Gene mutations that lead to channelopathies can be divided into several categories. According to Pancaroglu and Petegem (2018), those are “interfering with ion permeation, protein folding, voltage sensing, ligand and protein binding, and allosteric modulation of channel gating” (p. 373). Disorders connected to the muscles malfunction, more specifically excitation and contraction complexes, are also a result of channelopathies. The calcium that is present in the muscle fibers engages in the coupling process of excitation-contraction (EC) (Pancaroglu & Petegem, 2018).

In cardiac muscles, cytosolic Ca2+ plays the role of the primary activator for the RyR2 isoform (Pancaroglu & Petegem, 2018). This is connected to the L-type voltage-gated calcium channels, which allow for an influx of calcium upon depolarization. In the context of skeletal muscle, the mechanism of action differs drastically since calcium influx does not affect the initial opening of the RyR1 isoform. Notably, “RyRs are also sensitive to luminal Ca2+ levels, among which high levels may trigger spontaneous openings” (Pancaroglu & Petegem, 2018, p. 376).

The RyR1 and RyR2 isoforms were examined in this paragraph since they are often affected by the malfunction of the calcium cell channels. Pancaroglu and Petegem (2018) point out several conditions that develop as a result, including malignant hyperthermia (MH), central core disease (CCD), catecholaminergic polymorphic ventricular tachycardia (CPVT). CCD is a condition that results in muscle weakness and or abnormalities of the skeletal structures. CPVT is connected to the RyR2 mutation and can result in the sudden death of an individual due to cardiac failure. When examining the CPVT in particular, Pancaroglu and Petegem (2018) point out that the leakage of diastolic calcium, which results in an increase of cytosolic Ca2+. The sodium-calcium exchange is impaired by this issue, and one ion of Ca2+ is substituted by three ions of Na2+ (Pancaroglu & Petegem, 2018). In the context of CCD and MH, the increased sensitivity to calcium as a result of gene mutation is thought to provoke the condition. Therefore, the examined article outlines the primary mechanism of calcium channels and mutations of RyR1 and Ryr2 that can impair its functioning and lead to a loss of muscle’s capabilities.

Periodic paralysis is a condition that affects a person’s muscles by temporarily causing weakness, which develops as a result of genetic mutations and is also associated with the malfunctioning of the calcium channels. This disease is characterized by the variation on the serum potassium concentration that arises as a result of mutations in channel genes. Another article, which focuses on muscular disorders and molecular pathophysiology, is written by Platt and Griggs (2009), in which the authors summarize the main findings relating to the calcium channels functioning since the number of periodic paralysis cases continuously increases. The authors suggest that the gating mechanism of the channel pore is the primary reason that prompts this mutation. The role of gating pore is channelopathy, and its pathogenesis is thus more evident since the gating pore current affects the sodium channels in muscles and leads to leakage. Therefore, the leak within the ion channels, more specifically, the calcium channels, is defined as the leading cause of pathogenic mutations.

The normal function of the calcium channel within a muscle fiber is a response to depolarization, which results in EC coupling that was discussed in the previous paragraphs. This malfunction of the mechanism usually occurs as a result of mutation, since according to Platt and Griggs (2009), “the mutations replace arginine residues in the S4 voltage sensor in domains II, III, or IV with neutral amino acids” (p. 526). The main reason for this is the improper functioning of the gating pore and voltage sensor. The membrane depolarises, resulting in a sensitizing of myofibres and a decrease in potassium levels. The understanding of these mechanisms, as well as the technical advancements, allow for early diagnosis of these issues that affect the skeletal muscles and provide patients with access to better treatment.

Cardiological Disorders Connected to Calcium Channels Mutations

As was mentioned, calcium channels are present in different structures of the human body. Betzenhauser, Pitt, and Antzelevitch (2015) examined the impact of calcium channel mutation on the diseases of the cardiovascular system. An essential element of this system is the cardiac voltage-gated calcium channel (VGCC), which can be found in the membrane of an excitable cell. The excitability of a cell is a characteristic of cells that allows one to stimulate the theme with an electric current. Both muscle fibers and neuron cells allow for electric current stimulation.

The excitability of cells is linked to calcium since through the voltage transferred through cells. The connection between cell excitability and disease is a result of a malfunction of these cells. Therefore, calcium in excitable cells is an essential element of the electric current establishment, which is the primary property of these cells. Betzenhauser, Pitt, and Antzelevitch (2015) describe the mechanism of actin as follows – “the calcium that enters the cell during the action potential serves to trigger the release of Ca 2+ from internal sarcoplasmic reticulum (SR) stores via activation of type 2 ryanodine receptors” (p. 133). In this context, it is essential to understand the function of L-type VGCC, which allows calcium to pass to the cardiomyocyte. The impairment of the L-type CGCC leads to significant malfunctions of the cardiac system.

The paragraph above outlines the primary aspects of calcium channels that impact the functioning of the cardiovascular system. Yazava and Song (2017) support these conclusions and argue that mutations of the CaV1.2 lead to cardiac arrhythmia. The authors state that “G406R mutation (LQTS8, Timothy syndrome) affected channel inactivation, action potentials and calcium handling in human cardiomyocytes” (p. 10) However, some questions that require further explorations in order to fully understand the role of calcium in cardiac diseases still exist. Therefore, these studies support the hypothesis that calcium channels are essential in the context of the cardiovascular system. The mechanism of calcium channels in the heart is connected to the function of the T and L types of channels, responsible for transporting calcium into the cell membranes, with L-type being present in all cardiac cells.

Neurological Disorders Associated with Calcium Channels

In general, diseases connected to the ion channels have been examined by many researchers, and the recent advances in technology such as cryo-electron microscopy allow for a more detailed exploration of ion channel structures. This provides more insight into the different states of ion channels and the role of calcium in the functioning of different cells. Noebels (2017) argues that recent studies focus on the neurological properties of calcium channels and their connection to neurological disease development. Recent technological and scientific developments make it easier to detect the impairments of the structural variants in different channels. However, more research is necessary to precisely explain the complicated relationship between a single-channel function and physiology.

Absence epilepsy is a condition characterized by a person’s lack of presence for a duration of several seconds and usually affects children. Absence seizures are a subtype of epilepsy, which are also linked to channelopathies. The main factor that causes absence seizures is brain hyperventilation or decrease in PaCO2 and subsequent lowering of cerebral blood flow. This condition is also associated with the malfunction of the calcium channels. Zhang et al. (2002) examined the thalamic neurons to determine the impact of high voltage-activated calcium channel genes. Rhythmic bursts are generated as a result of Ca2+ currents activated by low voltages.

When these currents are generated in the thalamocortical circuitry, they result in abnormal rhythmicity, which causes the discussed condition. Zhang et al. (2002) state that “rhythmic burst firing characterizes cellular signaling behavior in the thalamus and depends on intrinsic membrane properties of thalamocortical relay (TC) neurons, as well as the synaptically linked neurons in the adjacent thalamic reticular nucleus (nRT)” (p. 6362). Spike-wave electrogenesis links the absence of epilepsy to the T-type pathway with the condition. Gene mutation of the Ca2+ units results in defective signaling and, therefore, epilepsy. The current research suggests that the exact mechanism, which would explain the functioning of the mutated calcium channels in the thalamic neurons is unclear. This research suggests that peak current density, as well as voltage dependence, result in burst firing. Therefore, the reviewed literature provides insight into the current research on neurological diseases and calcium changes. The findings of this paragraph highlight the main aspects of epilepsy that results from a calcium channel mutation.

Conclusion

Overall, this paper examined the role of calcium channels in disease. Varied channelopathies can occur as a result of gene mutation or other factors that lead to the development of different conditions, such as muscular, neurological, renal, or cardiovascular conditions. The examination of the calcium channels’ action and the leakage associated with their misfunction can lead to an improvement of treatment for conditions such as periodic paralysis. The gating pore misfunctions, and the subsequent leakage of calcium is found to be the primary cause of the channelopathies. In the context of the cardiovascular system, the CaV1.2 calcium channel mutations result in cardiac arrhythmia. Additionally, muscle diseases that lead to a temporary or permanent loss of function are the result of pore gating mechanism impairment that leads to a change in the serum potassium. In regards to the neurological implications of the calcium channels, the findings suggest that peak current density and depolarization are the main aspects that impact absence epilepsy.

References

Betzenhauser, M., Pitt, G., & Antzelevitch, C. (2015). Calcium channel mutations in cardiac arrhythmia syndromes. Current Molecular Pharmacology, 8(2), 133-142. Web.

Noebels, J. (2017). Precision physiology and rescue of brain ion channel disorders. The Journal Of General Physiology, 149(5), 533-546. Web.

Pancaroglu, R., & Van Petegem, F. (2018). Calcium channelopathies: Structural insights into disorders of the muscle excitation–Contraction complex. Annual Review of Genetics, 52(1), 10-59. Web.

Platt, D., & Griggs, R. (2009). Skeletal muscle channelopathies: new insights into the periodic paralyses and nondystrophic myotonias. Current Opinion in Neurology, 22(5), 524–531. Web.

Zhang, Y., Mori, M., Burgess, L., & Noebels, M. (2019). Mutations in high-voltage-activated calcium channel genes stimulate low-voltage-activated currents in mouse thalamic relay neurons. The Journal of Neuroscience, 22(15), 6362–6371.

Yazava, M. & Song, L. (2017). Cdk5 is associated in cardiac calcium channelopathy. Circulation Research, 119(1), 1-10.