The voltage-gated calcium channels (Cav Ion Channels)

An introduction to the voltage-gated calcium channels

Voltage-gated calcium channels (Ca_V ion channels) are a family of ion channels that play a critical role in calcium influx into cells. They are involved in various physiological processes, including neurotransmitter release and synaptic transmission, muscle contraction, hormone secretion, and gene expression. The Ca_V channels are classified into several subfamilies based on their subunit composition.

Ca_V channels are composed of multiple subunits, including the main pore-forming α1 subunit, along with auxiliary α2δ, β, and γ subunits. While the α1 subunit, which is encoded by various genes (listed in Table 1) contains the voltage-sensing domains, auxiliary subunits modulate the channel function, trafficking, gating kinetics, and pharmacology. The auxiliary subunits are encoded by separate genes:

• Genes belonging to the CACNB family encode the beta subunits. For example, CACNB2 encodes the beta-2 subunit, and CACNB3 encodes the beta-3 subunit.
• Genes belonging to the CACNA2D family encode the alpha2delta subunits. For example, CACNA2D1 encodes the delta-1 subunit, and CACNA2D2 encodes the delta-2 subunit.
• Genes belonging to the CACNG family encode the gamma subunits. For example, CACNG1 encodes the gamma-1 subunit, and CACNG2 encodes the gamma-2 subunit.

Regarding tissue distribution, Ca_V channels are expressed in various tissues and cell types throughout the body. For example, Ca_V1 channels are found in excitable cells such as neurons, cardiac muscle, and smooth muscle, while Ca_V2 channels are prominent in presynaptic terminals for neurotransmitter release. Ca_V3 channels are involved in pacemaker activity and rhythmic oscillations in neurons and cardiac cells.

Major groups	Members	Genes encoding the main subunit (alpha)	Species and tissues of expression *
CaV1 (L-type) channels	CaV1.1	CACNA1S	Primarily found in skeletal muscle cells of mammals.
CaV1.2	CACNA1C	Widely expressed in various tissues, including the heart, smooth muscle, and neurons of mammals.
CaV1.3	CACNA1D	Found in the heart, brain, and other tissues of mammals.
CaV1.4	CACNA1F	Mainly expressed in the retina and involved in visual signal transmission in mammals.
CaV2 (P/Q, N, and R-type) channels	CaV2.1 (P/Q-type)	CACNA1A	Expressed in neuroendocrine cells and in neurons (especially in cerebellar Purkinje neurons, which explains the “P-type” denomination, for “Purkinje”) in various species, including mammals, birds, and reptiles.
CaV2.2 (N-type)	CACNA1B	Found in neurons, particularly in the central nervous system of mammals.
CaV2.3 (R-type)	CACNA1E	Expressed in neurons, including those in the brain, spinal cord, and sensory ganglia, in mammals and other vertebrates.
CaV3 (T-type) channels	CaV3.1	CACNA1G	Expressed in neurons, including those in the brain, heart, and smooth muscle cells of mammals.
CaV3.2	CACNA1H	Found in neurons and neuroendocrine cells in various species, including mammals, birds, and reptiles.
CaV3.3	CACNA1I	Expressed in neurons, particularly in the brain, heart, and smooth muscle cells of mammals.

The expression of Ca_V channels can vary across different tissues and cell types within organisms. It’s worth noting that while some Ca_V channels may have similar names across species, there can be slight variations in their genetic sequences and functional properties.

Function and Activation:

Ca_V channels are primarily responsible for calcium influx in response to changes in membrane potential. Upon depolarization of the cell membrane, these channels open, allowing calcium ions to enter the cell. The activation and inactivation properties of Ca_V channels are finely regulated, enabling precise control over calcium signaling.

Here are some additional key mechanisms involved in the regulation of Ca_v channels:

• Intracellular Calcium Concentration: Calcium ions act as positive feedback regulators, promoting the opening of CaV channels and amplifying calcium influx. This mechanism is crucial for calcium-induced calcium release (CICR) processes and calcium signaling pathways.
• Phosphorylation: Protein kinases, such as PKA and PKC, can phosphorylate Ca_V channels, enhancing or inhibiting their function. Phosphorylation affects channel gating, trafficking, and interaction with auxiliary subunits. Calcium-dependent regulatory mechanisms activated by calcium entering through Ca_V channels also modulate their activity.

Understanding the intricate regulation of Ca_v channels by cellular signals and pathways is essential for comprehending their physiological roles and pathological implications. Metrion can support studies of these regulatory mechanisms to help gain insights into the modulation of Ca_v channel activity and explore potential therapeutic targets for various diseases.

Pathological Implications:

Dysfunction of Ca_V channels can lead to several diseases and disorders. Mutations in these channels have been linked to neurological disorders, cardiac arrhythmias, skeletal muscle disorders, and pain syndromes.

One example of a neuronal disorder involving Ca_V ion channels is familial hemiplegic migraine (FHM). FHM is a rare form of migraine with aura that is often caused by mutations in Ca_V2.1 channels, which are primarily encoded by the CACNA1A gene. These mutations can lead to aberrant channel function and dysregulated calcium signaling in neurons.

Another example of pathological implication of Ca_v channels is neuropathic pain. Ca_V2.2 (N-type calcium channels), are found in high abundance in sensory neurons and Ca_V2.2 upregulation have been implicated in the enhanced excitability of sensory neurons following peripheral nerve injury.

Ca_V1.2 plays a vital role in the human heart by regulating cardiac muscle contraction. Mutations in the gene encoding Ca_v1.2 can lead to a condition called Timothy syndrome, which is characterized by abnormal heart rhythms and other symptoms. Targeting Ca_V channels has emerged as a potential therapeutic strategy for the treatment of these conditions.

As part of Metrion Biosciences cardiac safety screening, we include Ca_v1.2 in our core cardiac panel and CiPA (Comprehensive in vitro Proarrhythmia Assay) evaluations. Using advanced electrophysiology techniques, Metrion assesses the effects of compounds on Cav1.2 channels to evaluate their potential impact on cardiac safety.

Metrion’s expertise on Ca_v ion channels:

At Metrion Biosciences, we specialize in studying ion channels and their role in cellular function and disease. Our experienced team has conducted extensive research to understand the properties and pharmacology of Ca_V channels.

Our services related to Ca_V ion channels include:

• Electrophysiology Studies: We use advanced techniques to investigate the biophysical properties of Ca_V channels, such as voltage-dependence, kinetics, and modulation by pharmacological agents. Our expertise allows us to accurately characterize the activity and behavior of these channels.
• High-Throughput Screening: Our screening platforms enable efficient evaluation of compounds for their effects on Ca_V channels. We assess compound potency, selectivity, and mode of action, aiding in the discovery of potential drug candidates.
• Pharmacological Profiling: We provide comprehensive profiling services to evaluate the effects of compounds on different Ca_V channel subtypes, helping to understand compound specificity and potential off-target effects. By including Cav1.2 in their cardiac panel, Metrion provides valuable data to support drug development efforts, ensuring safer and more effective medications.
• Disease and translational models: Using native tissues such as DRG or using translational models such as human iPSC-derived neurons or -cardiomyocytes, we can investigate the role of Ca_V channels in diseases such as pain and cardiovascular conditions. Our expertise allows us to explore mechanisms underlying diseases and identify therapeutic targets.

Conclusion:

Ca_V ion channels are essential regulators of calcium signaling in various physiological processes. Understanding their structure, function, and regulation provides insights into cellular and organ functions and their potential implications in disease states. Further research on Ca_V channels promises to uncover new therapeutic opportunities.

Fun fact

Spider venoms are a fascinating source of bioactive compounds, and one such compound is called ω-AGATOXIN IVA. It is derived from the venom of the funnel web spider (Agelenopsis aperta). ω-AGATOXIN IVA is a potent blocker of Ca_v2.1 (P/Q-type) calcium channels, which are involved in neurotransmitter release in the nervous system. This compound has been extensively studied for its therapeutic potential in neurological disorders and as a tool in scientific research to understand the role of Ca_v2.1 channels in neuronal signaling.

Through Metrion’s expertise and advanced technologies, we aim to accelerate the discovery and development of treatments targeting Ca_V ion channels. We collaborate closely with our clients, offering customized experiments and tailored solutions.