Application Area

Central Nervous 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 central nervous system (CNS), where they are widely distributed. Further advancing the field of electrophysiology, the advent and adoption of automated patch clamp systems has allowed researchers to investigate ion channels at an exponentially faster pace than manual patch clamp. 

The implications of ion channels in various neurological conditions cannot be overstated. EpilepsyataxiamigraineschizophreniaAlzheimer’s disease, and other neurodegenerative diseases have all been linked to dysfunctional ion channels.  Further exploring the role of ion channels in these areas may pave the way for innovative therapeutic interventions that can significantly improve the lives of individuals affected by these conditions.

Below, we highlight a key ligand and voltage-gated ion channels that have been shown to play a significant role in diseases of the central nervous system.

IonFlux systems are especially suited for research into neuronal voltage and ligand-gated ion channels. Ion channels can be transfected into recombinant cell lines or naturally expressed in primary cells or induced pluripotent stem cells (iPSC).

Important System Characteristics:

Nicotinic Acetylcholine Receptors

Nicotinic Acetylcholine Receptors (nAChRs) are expressed in both the peripheral and central nervous systems. nAChRs 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.

Gamma-aminobutyric acid Receptors

Gamma-aminobutyric acid receptors (GABARs) are the main inhibitory receptors in the CNS and mediate fast synaptic inhibition by opening Cl– channels. Mutations in GABAR genes can cause epilepsy, intellectual disability, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, and other neurodevelopmental disorders. Some drugs that target GABARs include baclofen, which is used to treat spasticity and alcohol dependence, and zolpidem, which is used to treat insomnia.

Glutamate Receptors

Glutamate receptors (GluRs) are the main excitatory receptors in the CNS and mediate fast synaptic transmission by opening Na+ and Ca2+ channels. GluRs consists of 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 contribute to the development of 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 and mediate fast inhibitory transmission by opening Cl channels. GlyR 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, which is 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 and mediate fast excitatory transmission by opening Na+, K+, and Ca2+ channels. They are activated by extracellular adenosine triphosphate (ATP), which is released from damaged or stressed cells. They 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.

Representative Channels

Sodium Channels

Voltage-gated Nachannels are essential for generating action potentials and propagating nerve impulses along axons. Mutations in Na+ channel genes can cause various forms of epilepsy, such as Dravet syndrome, generalized epilepsy with febrile seizures plus (GEFS+), and benign familial neonatal-infantile seizures (BFNIS). Some antiepileptic drugs, such as phenytoin and carbamazepine, act by blocking Na+ channels and reducing neuronal excitability.

Potassium Channels

Voltage-gated K+ channels are responsible for repolarizing the membrane after an action potential and modulating neuronal firing patterns. Mutations in K+ channel genes can also cause epilepsy, as well as ataxia, deafness, and developmental delay. For example, mutations in KCNQ2 and KCNQ3 genes, which encode subunits of the M-type Kchannel, can cause benign familial neonatal seizures (BFNS). Some antiepileptic drugs, such as retigabine, act by opening K+ channels and stabilizing the resting membrane potential.

Calcium Channels

Voltage-gated Ca2channels are involved in regulating intracellular Ca2+ levels and triggering neurotransmitter release at synapses. Mutations in Ca2+ channel genes can cause various neurological disorders, such as familial hemiplegic migraine (FHM), episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6), and Lambert-Eaton myasthenic syndrome (LEMS). Some drugs that target Ca2+ channels include gabapentin and pregabalin, which are used to treat neuropathic pain and anxiety.


Representative Channels

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Customer Spotlight

Potentiation of GABA receptors and idiopatic hypersomnia

IonFlux Mercury HT was recently used in a recent study correlating the existence of naturally occurring positive allosteric modulators of GABAA receptors in extracted cerebrospinal fluid of idiopathic hypersomnia patients. 

Application Spotlight

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. 

Application Spotlight

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.