L7 - Ion Channels

Signal Transduction

  • Presenter: Ben Gelfand, PharmD, PhD Student, Joint Graduate Program in Pharmacology and Toxicology

  • Contact: byg8@pharmacy.rutgers.edu

The Plasma Membrane

  • Structure:

    • The plasma membrane is a lipid bilayer, acting as an electrical insulator that prevents ions from passing through.

  • Function of Channels and Pumps:

    • Channels:

      • Facilitate the movement of ions down their electrochemical gradient via facilitated diffusion.

      • Selective for specific ions.

    • Pumps:

      • Employ active transport, which is ATP-dependent, to transport ions against their electrochemical gradient.

The Electrochemical Gradient

  • Definition:

    • Ions possess both a concentration gradient and an electrical gradient.

  • Electrochemical Gradient:

    • The composite of these two gradients is referred to as the electrochemical gradient.

    • Movement of ions across the membrane continues until the electrical and chemical gradients balance to zero.

Pumps

  • Sodium-Potassium Pump (Na+/K+ Pump):

    • Uses active transport to move sodium (Na+) and potassium (K+) ions against their electrochemical gradient.

    • Function:

      • Helps maintain resting membrane potential.

  • Mechanism of Action:

    1. Binding: Cytoplasmic Na+ binds to Na+/K+ pump.

    2. Phosphorylation: Pump phosphorylated by ATP, transitioning to a different conformation, which causes Na+ release.

    3. K+ Binding: Extracellular K+ binds, resulting in dephosphorylation.

    4. Return: The pump reverts to its original conformation.

Ion Channels Properties

  • Mechanism:

    • Ion channels operate via facilitated diffusion allowing ions to move down their concentration gradient.

  • Characteristics:

    • Selectivity is based on size and charge density of the ions.

    • Gating Mechanisms:

      • The opening/closing is influenced by stimuli.

      • Types of gating include:

      • Voltage-gated: Activation depends on membrane voltage.

      • Ligand-gated: Activation due to ligand binding.

      • Mechanically gated: Activated by physical stimuli such as stretch or heat.

Physiological Basis of Gating

  • Ion channel proteins alternate between open and closed states randomly.

  • The likelihood of an ion channel being open is defined as the probability (P_O) of being in the open state.

  • Certain stimuli positively or negatively adjust this probability.

  • Ligand-gated channels typically have a P_O near 100% upon ligand engagement.

Voltage-Gated Channel Structure

  • Structure comprises a single subunit, with a specific segment (S4) acting as a voltage sensor, reacting to voltage changes by moving within the membrane.

  • This movement regulates the opening or closing of the pore domain.

  • Ions translocate only when the pore is open, with four subunits assembling to form the active channel.

  • Reference: Börjesson, S.I., Elinder, F. (2008). "Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels." Cell Biochem Biophys, 52, 149–174.

Voltage-Gated Na+ Channels

  • Role:

    • Permit Na+ influx, contributing to depolarization.

    • Functionality: Promote positive feedback during depolarization, increasing the probability of Na+ channel opening as depolarization continues.

    • States:

      • Closed State initially, rapidly transitions to an inactivated state post-opening, even during membrane depolarization.

    • Repolarization is required before reopening can occur, crucial for neuronal and cardiac action potentials.

Voltage-Gated Na+ Channel States

  • Channel States Summary:

    • Resting: Closed; Activation Gate = Closed, Inactivation Gate = Open.

    • Open: Both gates are open.

    • Inactivated: Activation Gate = Open, Inactivation Gate = Closed.

  • Inactivated state achieved in nanoseconds, with necessary membrane repolarization leading to return to resting state, relating to action potential's refractory period.

Voltage-Gated K+ Channels

  • Function:

    • Maintain K+ efflux causing repolarization of the neuron.

    • Exception noted with KIR channels that permit K+ influx, assisting in recovery from hyperpolarization post-action potential.

  • Feedback Mechanism:

    • K+ reflux exerts negative feedback, where depolarization elevates the chances of K+ channels opening, advancing repolarization.

  • Types:

    • Fast-inactivating and slow-inactivating K+ channels both exist to contribute to action potential repolarization and termination.

Voltage-Gated K+ Channels and Cardiology

  • Importance:

    • hERG K+ channels are vital for cardiac repolarization.

    • Blockage extends action potential duration and QT interval, raising risks of ventricular arrhythmias.

    • Note: This topic is not part of exam materials.

Voltage-Gated Ca++ Channels

  • Functionality:

    • Allow Ca++ influx into cells without propagating action potentials.

    • Sparse voltage-gated Ca++ channels along axon; primarily located at synaptic terminals.

  • Conversion:

    • Upon activation, these channels facilitate neurotransmitter release in neurons and muscular contraction in muscle cells.

  • Variability:

    • Different types exist based on tissue distribution.

Ligand-Gated Ion Channels

  • Definition:

    • Ion channels that open or close in response to ligand binding.

  • Types of Ligands:

    • Natural ligands include neurotransmitters.

      • Not all neurotransmitters activate ligand-gated ion channel receptors.

      • Examples:

      • Acetylcholine

      • Serotonin

      • GABA

      • Glutamate

  • Importance:

    • Found at nervous system synapses and essential for rapid neuronal communication.

Acetylcholine (ACh)

  • Abbreviation:

    • Refers to acetylcholine.

  • Role in Body Systems:

    • Functioning in the neuromuscular junction, autonomic nervous system, parasympathetic nervous system, and central nervous system.

  • Effects:

    • In parasympathetic system:

      • Causes vasodilation, secretion increases from pancreas and salivary glands, decreased heart rate.

    • In neuromuscular junction: Facilitates skeletal muscle contraction, promoting rest-and-digest functions.

Acetylcholine Receptors

  • Receptor Types:

    • Nicotinic Receptors:

      • Ion channels; increased permeability to Na+ and K+.

    • M1, M3, M5 Types:

      • GPCRs; stimulate IP3, DAG pathways and increase intracellular Ca++.

    • M2, M4 Types:

      • GPCRs; affect cyclic AMP levels and increase permeability to K+.

    • Note: Only nicotinic ACh receptors function as ion channels.

Nicotinic Acetylcholine Receptors

  • Structure:

    • Composed of five subunits, including at least two alpha subunits which house the ligand binding site.

  • Mechanism:

    • Ligand binding prompts opening of the channel, allowing Na+ and K+ passage, causing depolarization of the postsynaptic cell.

  • Localization:

    • Dominantly present on presynaptic neurons in the CNS, facilitating ACh release.

    • Reference: Nara, S. et al., 2024, Cogn Neurodyn.

Serotonin (5-HT)

  • Definition:

    • Abbreviated as 5-HT (5-hydroxytryptamine).

  • Neurotransmitter Functions:

    • Operates within the CNS and enteric nervous system.

    • Involved in various brain functions, including mood, attention, sleep, appetite, and pain management.

  • Receptor Types:

    • Predominantly GPCRs with the exception of 5-HT3 receptor which functions as an ion channel.

    • 5-HT3 receptors play a role in CNS pathways associated with vomiting.

Serotonin Receptors

  • List of Receptor Types:

    • 5HT1A: GPCR; targets cyclic AMP and enhances K+ conductance.

    • 5HT1B: GPCR; influences cyclic AMP.

    • 5HT1D: GPCR; affects cyclic AMP and decreases K+ conductance.

    • 5HT2A: GPCR; uses IP3 and DAG to stimulate various ionic flows.

    • 5HT2C: GPCR; interrelated with IP3 and DAG pathways.

    • 5HT3: Ligand-gated ion channel; modulates flow of Na+, K+, Ca++.

5-HT3 Receptor

  • Structure:

    • Composed of five subunits, similar to nicotinic AChR.

  • Mechanism:

    • Ligand binding activates the ion channel, making it permeable to Na+, K+, Ca++, contributing to postsynaptic depolarization.

  • Clinical Relevance:

    • Antagonists of 5-HT3 receptors are primarily employed to manage nausea/vomiting.

    • Reference: Rammes, G. et al., 2004, Mol Psychiatry.

Amino Acid Neurotransmitters

  • Categories:

    • Glutamate: Principal excitatory neurotransmitter in CNS.

    • GABA: Main inhibitory neurotransmitter in the brain.

    • Glycine: Function can be context-dependent (inhibitory or excitatory).

Amino Acid Neurotransmitter Receptors

  • Glutamate Receptors: Types include:

    • Metabotropic: GPCRs utilizing IP3, DAG, or cyclic AMP pathways.

    • Ionotropic:

      • AMPA: Ion channel facilitating Na+ and/or Ca++ influx, crucial for rapid synaptic transmission.

      • Kainate: Ion channel similar to nicotinic/receptor channels permitting Na+ and K+ influx.

      • NMDA:

      • Ligand-dependent requiring both glycine and glutamate for activation, permeable to Na+, Ca++, and K+.

      • Mg++ acts as an endogenous inhibitor, playing a critical role in synaptic plasticity and memory.

  • GABA Receptors: Types include:

    • GABAA: Ligand-gated ion channel causing Cl- influx leading to postsynaptic hyperpolarization.

    • GABAB: GPCR incorporating IP3, DAG pathways affecting K+ and Ca2+ flows, also leading to hyperpolarization.