Application Area

Sensory & Pain System

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Over the past decade, our understanding of ion channel function has significantly advanced thanks to groundbreaking developments in molecular genetics and cellular electrophysiology. This newfound knowledge has shed light on the crucial role that ion channels play in the sensory nervous system, where they are widely distributed.

Sensory diseases related to ion channels are characterized by abnormal ion channel function, which disrupts the perception and processing of sensory information. Examples include channelopathies, such as congenital insensitivity to pain and paroxysmal extreme pain disorder, which are associated with mutations in sodium channels. Episodic ataxia types 1 and 2 are associated with mutations in potassium and calcium channels, respectively, leading to episodes of ataxia and other symptoms. Autosomal dominant sensory neuropathyhypokalemic periodic paralysis, and hereditary sensory neuropathy type 1 are also influenced by ion channel abnormalities. Understanding the genetic and molecular basis of these conditions is essential for diagnosis and development of therapeutic interventions.
 
IonFlux Mercury systems are especially well-suited for neuronal voltage-gated and ligand-gated patch clamp research. Ion channels can be transfected into recombinant cell lines or induced pluripotent stem cells (iPSC).

Important IonFlux Mercury Characteristics:

Nicotinic Acetylcholine Receptors

Nicotinic Acetylcholine (nAChRs) are expressed in both the peripheral and central nervous systems and mediate fast excitatory transmission at neuromuscular junctions and some synapses. Mutations in nAChR genes can cause congenital myasthenic syndromes (CMS), a group of disorders that impair neuromuscular transmission and cause muscle weakness. Some drugs that target nAChRs include nicotine, which is addictive and stimulates alertness and cognition, and varenicline, which is used to aid smoking cessation.

Glutamate Receptors

Glutamate receptors (GluRs) are the main excitatory receptors in the CNS and mediate fast synaptic transmission by opening Na+ and Ca2+ channels. They include three subtypes: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainate receptors. Mutations in GluR genes can cause epilepsy, intellectual disability, ASD, schizophrenia, and other neuropsychiatric disorders. Some drugs that target GluRs include ketamine, which is an anesthetic and antidepressant that blocks NMDA receptors, and memantine, which is used to treat Alzheimer’s disease by modulating NMDA receptor activity.

Glycine Receptors

Glycine receptors (GlyRs) are expressed mainly in the spinal cord and brainstem. GlyRs mediate fast inhibitory transmission by opening Cl channels. They are involved in regulating motor control, pain, and breathing. Mutations in GlyR genes can cause hyperekplexia, a disorder characterized by exaggerated startle responses and muscle stiffness. Some drugs that target GlyRs include strychnine, which is a potent convulsant and neurotoxin that blocks GlyRs, and glycine, a co-agonist of NMDA receptors and has neuroprotective effects.

P2X Receptors

P2X receptors (P2XRs) are expressed in both the peripheral and central nervous systems. P2XRs mediate fast excitatory transmission by opening Na+, K+, and Ca2+ channels. P2XRs are activated by extracellular adenosine triphosphate (ATP), which is released from damaged or stressed cells. Additionally, P2XRs are involved in regulating pain, inflammation, immune response, blood pressure, and neurotransmission. Mutations in P2XR genes can cause dysautonomia, a disorder that affects the autonomic nervous system. Some drugs that target P2XRs include suramin and pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), which are antagonists of P2XRs.

Transient Receptor Potential Channels

Transient receptor potential (TRP) channels are a diverse family of ion channels that are involved in various sensory modalities. TRP channels are activated by a wide range of stimuli, including temperature, touch, pain, and chemical signals. TRP channels are found in both the peripheral sensory neurons and the central nervous system. Examples include: TRPV1, a TRP channel that is activated by heat, capsaicin (the compound responsible for the “heat” in chili peppers), and various inflammatory mediators. TRPV1 is involved in nociception (pain perception) and is known as the “capsaicin receptor.” Activation of TRPV1 channels leads to the sensation of heat and pain. TRPM8 is a TRP channel that is activated by cold temperatures and cooling compounds such as menthol. TRPM8 plays a role in cold sensation and is known as the “cold and menthol receptor.” TRPA1 is a TRP channel that is activated by various chemical irritants, such as mustard oil and environmental pollutants. TRPA1 is involved in nociception and is known as the “irritant receptor.”
 

Representative Channels

Sodium Channels

Voltage-gated sodium channels (Nav channels) are responsible for the initiation and propagation of action potentials in sensory neurons. In the context of pain, Nav channels are critical for the generation and transmission of nociceptive signals, as they play a critical role in the initial depolarization and firing of neurons in response to painful stimuli. Nav1.7, Nav1.8, and Nav1.9 are specific subtypes of Nav channels that are highly expressed in sensory neurons and are involved in pain signaling. Mutations or dysregulation of Nav channels can lead to altered pain perception. For example, gain-of-function mutations in Nav1.7 are associated with familial episodic pain syndromes, while loss-of-function mutations can cause congenital insensitivity to pain.

Potassium Channels

Voltage-gated potassium channels (Kv channels) are responsible for repolarization and the restoration of resting membrane potential after an action potential. Kv channels play a role in shaping the firing properties of sensory neurons and regulating neuronal excitability. Dysfunction of Kv channels can contribute to altered pain sensitivity. For example, mutations in Kv1.1 channels are associated with episodic ataxia type 1, a condition that includes symptoms of pain and sensory disturbances.

Calcium Channels

Voltage-gated calcium channels (Cav channels) are involved in calcium influx, which is critical for various cellular processes, including neurotransmitter release. Cav channels play a role in synaptic transmission and modulation in the sensory nervous system, influencing pain processing. Certain subtypes of Cav channels, such as Cav2.2 and Cav2.1, are involved in transmitting nociceptive signals and regulating pain sensitivity.

Chloride Channels

Voltage-gated chloride channels (ClC channels) regulate chloride ion influx and efflux, contributing to membrane potential and neuronal excitability. Dysregulation of ClC channels can influence pain perception. For example, mutations in the ClC-2 chloride channel have been associated with idiopathic generalized epilepsy, a condition that can include pain as a symptom.
 

Representative Channels

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Article Highlight

Nebivolol as a Potent TRPM8 Channel Blocker: A Drug-Screening Approach through Automated Patch Clamping and Ligand-Based Virtual Screening

In this featured article, Jahanfar et al. aimed to discover novel transient receptor potential melastatin 8 (TRPM8) blocking agents. The TRPM8 ion channel has been implicated in various conditions, including neuropathic pain and cancer. The investigators leveraged the IonFlux Mercury to screen and determine the EC50 for a subset of 12 sodium ion channel blockers and 7 β-blockers.

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Investigating Potent Blockers of TRPM8

IonFlux 16 was used in a recent study aiming to discover novel TRPM8 channel block using automated patch clamp combined with ligand-based virtual screening.

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Screening positive allosteric modulators for NMDA Receptors

NMDAR hypofunction is implicated in the pathophysiology of schizophrenia. Positive allosteric modulators (PAMs) are molecules capable of enhancing a receptor’s signal. In a recent study, IonFlux HT technology was used in a screening pipeline to identify GluN2A selective NMDAR PAMs. 

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Identifying potential analgesic candidates

Glycine receptors play a key role in mediating inhibitory neurotransmission and hence contribute to the regulation of pain signaling in the dorsal horn. This recent study used IonFlux HT technology to identify positive allosteric modulators for GlyRα3.