Browse the corpus

Calcium channels play an essential critical role in a variety of physiological functions in cells. They include all pore-forming membrane proteins that are calcium-permeable and used for the transport of these ions across cell membranes. As an ion, calcium is unique in biological systems; this is because calcium not only functions to generate membrane potentials and electrical signals but also functions as a central cell signaling molecule. Therefore, calcium channels play an even more involved role in the cell by allowing for the generation of a multitude of cellular responses. Calcium channels come in many forms and are incredibly diverse in both structure and function.[1] Furthermore, there are a variety of methods by which they may be categorized. To provide an overview of calcium channels, it is necessary to describe the different types of calcium channels, their structures, functions in cellular responses, pharmacological properties, and associated pathologies. This article will attempt to summarize this diverse class of proteins to elucidate their nature at the molecular, cellular, tissue, and organismal levels.

Calcium channels appear to be involved in the pathophysiology of chronic pain. Synaptic nerve terminals located in the dorsal horn of the spinal cord receive action potentials propagating through primary afferent fibers, which occur upon activation of peripheral nociceptors in different organs and the skin. Pain is perceived when neurons activate in higher brain areas upon receiving an excitatory synaptic transmission from these dorsal horn synaptic terminals. The neuronal excitability of the afferent fibers is known to be regulated by Cav3.2 T-type VGCCs. Furthermore, neurotransmission in dorsal horn synapses is controlled by both Cav2.2 and Cav3.2 channels. In chronic pain conditions, these calcium channel subtypes have been shown to be upregulated.[21] Voltage-gated calcium channels are thought to be involved in the pathophysiology of seizures, including absence seizures. Cav3.1 and Cav3.2 channels, for example, are expressed on thalamocortical and reticular thalamic neurons, and alterations in their activity have been shown to result in absence seizures, which may occur as a result of various mutations in these channels. Specific seizure disorders have links with specific calcium channels. For example, juvenile myoclonic epilepsy and juvenile absence epilepsy are associated with Cav3.2 (T-type) channel mutations. Importantly, more than 30 mutations have been found in just the Cav3.2 a1 subunit gene alone that have correlations with various types of epilepsies. Also, gain-of-function mutations have been found to affect the gating activity and plasma membrane trafficking of these channels. Increased seizure susceptibility associated with overexpression or overactivity of these channels also makes them an important target for treating absence seizures. Absence seizures are one of the hallmarks of idiopathic generalized epilepsy, which accounts for one-third of all epilepsies.[21]

Voltage-gated calcium channels are thought to be involved in the pathophysiology of seizures, including absence seizures. Cav3.1 and Cav3.2 channels, for example, are expressed on thalamocortical and reticular thalamic neurons, and alterations in their activity have been shown to result in absence seizures, which may occur as a result of various mutations in these channels. Specific seizure disorders have links with specific calcium channels. For example, juvenile myoclonic epilepsy and juvenile absence epilepsy are associated with Cav3.2 (T-type) channel mutations. Importantly, more than 30 mutations have been found in just the Cav3.2 a1 subunit gene alone that have correlations with various types of epilepsies. Also, gain-of-function mutations have been found to affect the gating activity and plasma membrane trafficking of these channels. Increased seizure susceptibility associated with overexpression or overactivity of these channels also makes them an important target for treating absence seizures. Absence seizures are one of the hallmarks of idiopathic generalized epilepsy, which accounts for one-third of all epilepsies.[21] All addictive drugs share a common underlying pathophysiology in addiction in that they all can increase dopamine in the mesolimbic dopamine system and change CREB-dependent gene expression in the ventral segmental area and nucleus accumbens, whether it be through activation of opioid receptors (opioids), nicotinic receptors (nicotine), GABA receptors (alcohol, barbiturates, benzodiazepines) or dopamine receptors (stimulants). Voltage-gated calcium channels are involved in these processes, which lead to several important neurobiological and behavioral changes associated with addiction. For example, changes in neuroplasticity associated with stimulant abuse appear to involve the CaV1 family of voltage-gated calcium channels. Increased glutamatergic activity on the VTA occurs upon activation of Cav1.3 channels resulting from chronic exposure to psychostimulants.

All addictive drugs share a common underlying pathophysiology in addiction in that they all can increase dopamine in the mesolimbic dopamine system and change CREB-dependent gene expression in the ventral segmental area and nucleus accumbens, whether it be through activation of opioid receptors (opioids), nicotinic receptors (nicotine), GABA receptors (alcohol, barbiturates, benzodiazepines) or dopamine receptors (stimulants). Voltage-gated calcium channels are involved in these processes, which lead to several important neurobiological and behavioral changes associated with addiction. For example, changes in neuroplasticity associated with stimulant abuse appear to involve the CaV1 family of voltage-gated calcium channels. Increased glutamatergic activity on the VTA occurs upon activation of Cav1.3 channels resulting from chronic exposure to psychostimulants. The activity of Cav1.3 channels, along with increased glutamatergic activity in the VTA, causes NMDA and AMPA receptor-dependent changes in gene expression, which involves the upregulation of Cav1.2 receptors in VTA neurons. Since the firing behavior of neurons in the VTA is differentially regulated by Cav1.2 and Cav1.3 channels, dopamine release is increased onto the D1 receptors of the NAc. This activity leads to the insertion of AMPA receptors onto the NAc neuron plasma membranes and mediates long-term changes in gene expression. Ultimately, these activities have been linked to behavioral sensitization to psychostimulants.[21] Mutations in STIM and Orai are both associated with pathological diseases. Both gain and loss of function mutations lead to numerous pathologies.[40] For example, defects in the ability to form the CRAC channel are associated with severe combined immunodeficiency (SCID). The formation of Store-operated calcium channels is essential for T-cell lymphocyte function. Mutations in these channel proteins cause a reduction in the ability of T-cells to produce cytokines and may result in serious infections during infancy.[37] Other pathologies associated with abnormal or inactive SOCE function are myopathies and ectodermal dysplasia.[40]

Mutations in STIM and Orai are both associated with pathological diseases. Both gain and loss of function mutations lead to numerous pathologies.[40] For example, defects in the ability to form the CRAC channel are associated with severe combined immunodeficiency (SCID). The formation of Store-operated calcium channels is essential for T-cell lymphocyte function. Mutations in these channel proteins cause a reduction in the ability of T-cells to produce cytokines and may result in serious infections during infancy.[37] Other pathologies associated with abnormal or inactive SOCE function are myopathies and ectodermal dysplasia.[40] Adrenergic receptors are important physiological mediators of both cardiovascular and smooth muscle activity. They are especially significant pharmacologically as they are the targets of a variety of drug classes, such as beta-blockers, alpha-blockers, and alpha-adrenergic receptor agonists. Epinephrine, a general adrenergic receptor activator, has a significant influence on cardiovascular and smooth muscle activity. This activity occurs in part through its actions on both the plasma membrane and intracellular calcium channels. In cardiac muscle, beta-adrenergic receptors are targeted by epinephrine and produce positive chronotropic, inotropic, and dromotropic physiological effects, which are mediated by their ability to increase the opening time of voltage-gated calcium channels. In vascular smooth muscle, both contraction and vascular tone are increased by norepinephrine by alpha-receptor activation due to its ability to increase cytosolic calcium levels through a depolarization-independent IP3-receptor-mediated mechanism.[45][46][47]