Lect 4 Modulators of Neuronal excitability PDF

M33319 - Applied Pharmacology of the Nervous and Endocrine System Modulators of Neuronal Excitability Ngan Pan Bennett Au, PhD Lecturer in Pharmacology (Neuroscience) School of Pharmacy and Biomedical Science, University of Portsmouth...

M33319 - Applied Pharmacology of the Nervous and Endocrine System Modulators of Neuronal Excitability Ngan Pan Bennett Au, PhD Lecturer in Pharmacology (Neuroscience) School of Pharmacy and Biomedical Science, University of Portsmouth 1 Learning objectives Identify the various classes of drugs that target axonal voltage-gated ion channels, and their mechanisms of action in altering neuronal activity. Identify the various classes of drugs that target monoaminergic neurotransmitters/receptors/transporters, and their mechanisms of action in altering neuronal activity. Identify the appropriate clinical indications for these different drugs. 2 Drugs that will be covered in this lecture Drugs targeting axonal voltage-gated ion channels Drugs targeting monoaminergic neurotransmitters 3 Types of voltage-gated ion channels Voltage-gated sodium (Nav) ion channels Voltage-gated potassium (Kv) ion channels Voltage-gated calcium (Cav) 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 4 Voltage-gated sodium channels 10 different Nav identified in mammals Nav1.1 - Nav1.9 and atypical NavX Based on the difference in α-subunit · All are expressed in nervous system, except Nav1.4 CNS: Nav1.1 - Nav1.3, Nav1.5, Nav1.6 PNS: Nav1.7 - Nav1.9 α-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 TTX (tetrodotoxin)-sensitive: Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6, Nav1.7 TTX-resistant: Nav1.5, Nav1.8, Nav1.9 3 intracellular loops 5 Voltage-gated sodium channels β-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) 6 Modulators of voltage-gated sodium channels Phenytoin Act as a non-specific sodium channel blocker Stabilise the Nav channels that are inactivated Prolong the refractory period of a neuron 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 Medical indication Epilepsy/seizures following neurosurgery or severe head injury 7 Modulators of voltage-gated sodium channels Carbamazepine Act as a 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 Medical indication Epilepsy Trigeminal Neuralgia (sudden and severe facial pain caused by compression of trigeminal nerve) Mania (abnormally elevated arousal and energy level) 8 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. Five 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 9 Voltage-gated calcium channels Five types of Cav: 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) 10 11 Modulators of voltage-gated calcium channels Ethosuximide Block T-type calcium channels T-type calcium channels are: 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 Medical indications treatment of absence seizures 12 Modulators of voltage-gated calcium channels 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 Medical indications Epilepsy Neuropathic pain Spasticity (rigid muscles) in multiple sclerosis 13 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 14 Modulators of voltage-gated potassium channels 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 Medical indication Effective in treating various forms of epilepsy Withdrawal due to the development of blue discolouration of the skin and eye abnormality 15 16 5-Hydroxytryptamine (5-HT) pathways 17 5-Hydroxytryptamine (5-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) 18 Serotonin receptors 19 20 Modulators of 5-HT1 receptors 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 Medical indication short-term use for anxiety 21 Modulators of 5-HT1 receptors 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 Medical indication acute migraine acute cluster headache 22 Modulators of 5-HT3 receptors Ondansetron & Granisetron Antagonist of 5-HT3 receptors 5-HT3 receptors are ionotropic and cause activation without second messenger (i.e. neuronal excitation) 5-HT3 receptors are highly expressed in vagal nerve afferents 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 Medical indication Antiemetic drugs for chemotherapy or radiotherapy Prevention and treatment of postoperative nausea and vomiting 23 Modulators of dopamine D2 receptors 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) Medical indication 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 24 Modulators of dopamine D2 & 5-HT receptors 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 Medical indication Antiemetic drugs for chemotherapy or radiotherapy Prevention and treatment of postoperative nausea and vomiting 25 Modulators of dopamine D2 & 5-HT receptors 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) Classified as second-generation antipsychotic drugs 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 Medical indication Schizophrenia and other psychoses Mania Aggressive behaviours in moderate and severe Alzheimer’s disease patients 26 Selective serotonin reuptake inhibitors (SSRIs) Depression is caused by decreased serotonergic and noradrenergic neurotransmission SSRI binds to serotonin Activation of 5-HT1A receptors transporter (SERT) inhibit firing of 5-HT neurons Increased 5-HT in synaptic space 27 Selective serotonin reuptake inhibitors (SSRIs) Decreased number of 5-HT1A receptors: Increased 5-HT stimulation causes decreased inhibitory influence to 5-HT down-regulation of 5-HT1A neurons, increased activity and receptors increased 5-HT release 28 Modulators of serotonin transporter (SERT) 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 (why?) Medical indication Major depression Bulimia nervosa (eating disorder: consume a large amount of food but purging to get rid of it) Obsessive-compulsive disorder (OCD) 29 Thank you! 30