Modulators of Neuronal Excitability

• Types of Voltage-Gated Ion Channels


  • Voltage-gated sodium (Nav) ion channels
  • Voltage-gated potassium (Kv) ion channels
  • Voltage-gated calcium (Cav) ion channels
• Voltage-gated ion channels


  • Abundantly expressed in axon initial segment (AIS) - Determine the threshold for firing an action potential
  • Action potential propagates along the axon and reach the axonal terminal - Activate Cav - Calcium influx and neurotransmitter release
• Nav Channels Identified in Mammals

  • Nav1.1 - Nav1.9 and atypical NavX
• Nav Channels


  Based on the difference in α-subunit
• Nav Channels Expressed in CNS and PNS

  • CNS: Nav1.1 - Nav1.3, Nav1.5, Nav1.6
  • PNS: Nav1.7 - Nav1.9
• Nav Channel Alpha Subunit

  • 260 kDa - Pore Forming
  • 4 homologous transmembrane domain I-IV
  • Each domain has six hydrophobic α-helical transmembrane segments (S1-S6)
  • S4: voltage sensor (change in membrane potential) - related to activation of Nav
• Nav Channels Sensitivity to TTX

  • TTX-sensitive: Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6, Nav1.7
  • TTX-resistant: Nav1.5, Nav1.8, Nav1.9
• Nav Channel Beta Subunit


  • 33-36 kDa: auxiliary subunits
  • Contains three major parts: Independent transmembrane domain, Small intracellular C-terminal, Large intracellular N-terminal
  • 4 subtypes: β1-β4
  • Regulate α-subunit (gated kinetics, voltage-dependence, localisation)
• Phenytoin


  • Non-specific sodium channel blocker
  • Stabilise the Nav channels that are inactivated
  • Prolong the refractory period of a neuron
• Conditions Treated with Phenytoin


  • Epilepsy/seizures following neurosurgery or severe head injury
• Phenytoin Mechanism of Action

  • Blockade of sodium-dependent action potentials depends on - Voltage: Nav inactivated at positive (+30mV) membrane potential
  • Use: ultimately reduce sustained high-frequency firing of action potential
  • Time: time required to dissociate from binding of the drug to Nav channels
  • Reduce synaptic release of glutamate
• Carbamazepine


  • Non-specific sodium channel blocker
  • Also bind to other voltage-gated ion channels (e.g. Cav channels)
  • Stabilise the Nav channels that are inactivated
  • Prolong the refractory period of a neuron
  • Fewer Nav channels to open and prevent the generation of action potential
  • Reduce neuronal excitability
• Conditions Treated with Carbamazepine

  • Epilepsy
  • Trigeminal Neuralgia (sudden and severe facial pain caused by compression of trigeminal nerve)
  • Mania (abnormally elevated arousal and energy level)
• Voltage Gated Calcium Channels

  • Ca2+: second messenger within the cells for regulation of many signalling pathways
  • Cav: activate upon membrane depolarisation and mediate Ca2+ influx in response to action potentials and sub-threshold depolarisation signals
• Cav Subunits


  • α1: pore-forming subunit; 4 homologous I-IV domain (each contains 6 transmembrane helices S1-S6); voltage-sensing
  • α2δ: disulfide-linked glycoprotein dimer; drug target for gabapentinoids
  • β: intracellular subunit; stabilise the conformation of α1
  • γ: transmembrane glycoprotein subunit
• Types of Cav Channels

  • L-type (long-lasting via DHP receptors)
  • N-type (neural; found in brain and PNS)
  • P-type (Purkinje; cerebellum)
  • R-type (residual; cerebellar granule cells and neurons)
  • T-type (transient; many neurons, cells with pacemaker activity; thalamus)
• Ethosuximide


  Block T-type calcium channels
• Conditions Treated with Ethosuximide


  • Treatment of absence seizures
• 1. type Calcium Channels


  • Low-threshold calcium spikes: appear when neuronal membrane potentials are below -69mV
  • Amplitude of depolarisation is ~25mV: raise the membrane potential to -40mV
  • Opening of Nav: burst of action potential
  • Burst-firing is observed in rodent models of absence epilepsy
• Gabapentin


  • Ligand of α2δ calcium channel subunit (modulate α1 functions and stabilize cellular localisation of Cav)
  • Bind to α2δ and impair its regulatory functions and protein-protein interactions with other proteins
  • Block the translocation of Cav towards the cell membrane
  • Lower the amount of functional Cav at presynaptic terminals
  • Reduce neurotransmitter release & neuronal excitability
• Conditions Treated with Gabapentin

  • Epilepsy
  • Neuropathic pain
  • Spasticity (rigid muscles) in multiple sclerosis
• Voltage Gated Potassium Channels

  • Consists of six transmembrane helices S1-S6
  • S1-S4: Voltage sensor (sensing the change in membrane potential)
  • S5-S6: channel pore
  • Kv opens in response to depolarisation upon action potentials
  • K+ ions leave the cells: become more negative inside the cells (hyperpolarisation)
  • Decrease the probability of an action potential being generated
  • Decreased neuronal activity
• Retigabine


  • Bind to Kv7 potassium channels
  • Cause the opening of Kv
  • Increase the conductance of K+ ions out of the cells
  • Increase the hyperpolarization state of the cells
  • Decrease the probability of firing an action potential
  • Decrease neuronal excitability
• Conditions Treated with Retigabine


  • Effective in treating various forms of epilepsy
• Retigabine was withdrawn due to the development of blue discolouration of the skin and eye abnormality
• 1. HT Pathways


  • Serotonergic neurons are confined almost exclusively in raphe nuclei
  • Caudal cluster: medulla & spinal cord
  • Dorsal raphe nuclei project into cerebral cortex, thalamus, striatum, dopaminergic nuclei (SNr and VTA)
  • Medial raphe nuclei project into hippocampus, septum and limbic forebrain (motivation, emotion, learning and memory)
• Buspirone


  • Partial agonist of 5-HT1A receptors (mood and behaviour)
  • 5-HT1A receptors function as auto-receptor; express on the same cell that releases 5-HT
  • Activation of auto-receptors expressed in presynaptic terminals reduces local synthesis and release of 5-HT
  • Buspirone activates 5-HT1A receptors and decreases further 5-HT release
• Conditions Treated with Buspirone

  • Short-term use for anxiety
• Sumatriptan


  • Agonist of 5-HT1B/D receptors
  • Sumatriptan mimics the role of serotonin in binding to 5- HT1B/D receptors in trigeminal nerve endings
  • Decrease the pain and inflammatory mediator production (e.g. CGRP/substance P)
  • Induce vasoconstriction to relieve pain associated with migraine
• Conditions Treated with Sumatriptan

  • Acute migraine
  • Acute cluster headache
• Ondansetron & Granisetron


  • Antagonist of 5-HT3 receptors
  • 5-HT3 receptors are ionotropic and cause activation without second messenger (i.e. neuronal excitation )
  • 5-HT 3 receptors are highly expressed in vagal nerve a fferents and medulla (vomiting centre and chemoreceptor trigger zone)
  • Both drugs block the activity of vagal afferents connected to the vomiting centre
  • Both drugs block the activation of neurons in chemoreceptor trigger zone
• Conditions Treated with Ondansetron & Granisetron


  • Antiemetic drugs for chemotherapy or radiotherapy
  • Prevention and treatment of postoperative nausea and vomiting
• Haloperidol


  • Antagonist of dopamine D2 receptors
  • Block the dopamine D2 receptors in chemoreceptor trigger zone in medulla
  • Block the dopamine D2 receptors in the striatum (elevated in schizophrenia patients)
• Conditions Treated with Haloperidol


  • Antiemetic drugs for chemotherapy or radiotherapy
  • Prevention and treatment of postoperative nausea and vomiting
  • Schizophrenia and schizoaffective disorder
  • Manic episodes (abnormally elevated, extreme changes in mood and emotions) associated with bipolar I disorder
• Metoclopramide


  • Antagonist of dopamine D2 receptors and 5-HT3 receptors
  • Block dopamine D2 receptors and 5-HT3 receptors in chemoreceptor trigger zone
  • Agonist of 5-HT4 receptor for increased gastrointestinal motility: improved gastric emptying
• Conditions Treated with Metoclopramide


  • Antiemetic drugs for chemotherapy or radiotherapy
  • Prevention and treatment of postoperative nausea and vomiting
• Risperidone


  • Antagonist of dopamine D2 receptors and 5-HT2A receptors
  • Have affinity to 5-HT2A > D2 > α1-adrenergic > α2-adrenergic > Histamine H1 receptors (decreasing affinity)
  • Blocking 5-HT2A receptors enhances dopamine release in striatum by lowering the inhibitory effects of 5-HT: reduce negative symptoms
  • Combined D2 and 5-HT2A antagonisms counteract the increased dopamine functions: reduce positive symptoms
• Conditions Treated with Risperidone

  • Schizophrenia and other psychoses
  • Mania
  • Aggressive behaviours in moderate and severe Alzheimer's disease patients
• Selective Serotonin Reuptake Inhibitors (SSRIs)


  • Depression is caused by decreased serotonergic and noradrenergic neurotransmission
  • Activation of 5-HT1A receptors inhibit firing of 5-HT neurons
  • SSRI binds to serotonin transporter (SERT)
  • Increased 5-HT in synaptic space
  • Increased 5-HT stimulation causes down-regulation of 5-HT1A receptors
  • Decreased number of 5-HT1A receptors: decreased inhibitory influence to 5-HT neurons, increased activity and increased 5-HT release
• Sertraline & Fluoxetine


  • Bind selectively to serotonin transporter (SERT)
  • Block the reuptake of 5-HT at the synaptic cleft
  • Increase 5-HT transmission
  • Immediately increase the level of 5-HT at the synapses
  • Need 2-4 weeks of continuous treatment to manifest the clinical effects