Ligand-Gated Ion Channels Overview

Ligand-Gated Ion Channels

• Ligand-gated ion channels (LGICs) are transmembrane proteins that act as receptors and ion channels.
• LGICs are composed of receptor subunits that surround a central pore.
• The receptor itself acts as the ion channel, allowing the flow of ions down their concentration gradient.
• The timescale for LGIC activation is milliseconds.
• LGICs are involved in rapid synaptic transmission and neurotransmission.

Ligand-Gated Ion Channel Examples

• Examples of LGICs and their ligands include:
  • 5-HT3 receptors for serotonin (5-HT)
  • Nicotinic acetylcholine receptors (nAChR) for acetylcholine (ACh)
  • GABAA receptors for GABA
  • AMPA, Kainate, and NMDA receptors for glutamate
  • P2X receptors for ATP (purinergic receptors)

Ligand-Gated Ion Channel Regulation

• LGICs can be regulated by desensitization, where the receptor transitions to a state with higher affinity for the agonist, reducing channel activity.

Receptor Tyrosine Kinases (RTKs)

• RTKs are transmembrane proteins that have an extracellular domain for ligand binding, a single transmembrane helix, and an intracellular domain with tyrosine kinase activity.
• When a ligand binds to the extracellular domain, it triggers autophosphorylation of tyrosine residues in the intracellular domain.
• The phosphorylation pattern activates downstream signaling pathways.

RTK Signal Transduction

• Adapter proteins, like Grb2, bind to phosphorylated tyrosine residues on activated RTKs.
• Grb2 has SH2 and SH3 domains, which interact with specific motifs on other signaling molecules.
• Grb2 acts as a bridge, linking activated RTKs to downstream signaling pathways.

Ras Cell Signalling

• Activated Ras protein triggers a cascade of downstream signaling events.
• This cascade leads to changes in protein activity and gene expression, ultimately affecting cell proliferation and other cellular processes.

Tyrosine Kinase-Linked Receptors: Variation on a Theme

• Tyrosine kinase-linked receptors (TKLRs) are similar to RTKs, but with variations in structure and signaling.
• Instead of direct tyrosine kinase activity, TKLRs rely on associated kinases for downstream signaling.

Nuclear Receptors

• Nuclear receptors are intracellular proteins that regulate transcription by binding to specific DNA sequences.
• Two main types of nuclear receptors:
  • Homodimers: Bind to DNA as dimers, with both subunits derived from the same gene (e.g., estrogen receptor, progesterone receptor).
  • Heterodimers: Bind to DNA as dimers, with one subunit from the receptor gene and the other from the retinoid X receptor (RXR) gene (e.g., thyroid hormone receptor, retinoic acid receptor).

Homodimeric Nuclear Receptors

• Homodimers are typically located in the cytoplasm.
• Agonist binding facilitates their translocation to the nucleus.
• They bind to specific DNA sequences known as hormone-responsive elements (HREs).
• Binding to HREs can either activate or repress gene expression.

Heterodimeric Nuclear Receptors

• Heterodimers are typically located in the nucleus.
• They bind to specific DNA sequences known as response elements.
• Binding to response elements can either activate or repress gene expression.
• They are responsible for the regulation of various cellular processes, including development, metabolism, and hormone response.

Summary

• Ligand-gated ion channels, G-protein coupled receptors, tyrosine kinase-linked receptors, and intracellular receptors are all involved in signaling pathways that regulate various cellular functions.
• These receptors differ in their structure, mechanism of activation, and downstream signaling pathways.
• Together, they play a critical role in cellular communication and response to environmental stimuli.

Ligand-Gated Ion Channels

• Ligand-gated ion channels (LGIC) contain subunits around a central pore.
• The receptor itself acts as the ion channel, allowing flow down a concentration gradient.
• LGICs are fast acting with a timescale of milliseconds.
• Examples of LGICs include: 5-HT3 receptors for serotonin, nicotinic receptors for acetylcholine, GABAA receptors for GABA, AMPA, Kainate, and NMDA receptors for glutamate, and P2X receptors for purines.
• Desensitization occurs when the receptor enters a state with higher affinity for the agonist.

Receptor Tyrosine Kinases (RTKs)

• RTKs possess an extracellular domain that binds ligands, a single transmembrane helix, and an intracellular domain for tyrosine phosphorylation.
• The insulin receptor is an atypical example of an RTK.
• Adapter proteins bridge signaling molecules without initiating signaling themselves.
• Grb2, an adapter protein, binds to phosphorylated tyrosine residues on active receptors via its SH2 domain and recognizes proline residues on signaling molecules via its SH3 domain.
• Activated Ras proteins initiate various cell signaling pathways, leading to alterations in protein activity and gene expression.

Tyrosine Kinase-Linked Receptors (TKLRs)

• TKLRs display variations in their receptor:ligand stoichiometry.
• TKLRs can be categorized into five groups: TNF-alpha and related molecules, IL-1 family members, TGF-betas, factors signaling through receptor tyrosine kinases, and others.

Nuclear Receptors

• Nuclear receptors bind DNA as dimers and require phosphorylation for activation.
• Homodimeric nuclear receptors exist in the cytoplasm and include receptors for estrogen, progesterone, androgen, glucocorticoid, and mineralocorticoid.
• Heterodimeric nuclear receptors exist in the nucleus and join with retinoid X receptor (RXR). Examples include receptors for thyroid hormone and retinoic acid.
• Homodimer half-sites are inverted repeats, while heterodimer half-sites are direct repeats.
• Spacing between half-sites determines recognition for different receptors.
• Example of homodimer half-site: AGGACA(Nx)TGTCCT
• Example of heterodimer half-site: TGACCT(Nx)TGACCT
• Homodimers are involved in processes like gene transcription, while heterodimers mediate responses to various ligands like vitamin D, retinoic acid, and triiodothyronine.

Summary

• Ligand-gated ion channels are receptors that act as ion channels and rapidly transmit signals.
• G-protein coupled receptors (GPCRs) initiate signaling via G protein activation.
• Tyrosine kinase-linked receptors (TKLRs) are activated through ligand-induced phosphorylation of tyrosine residues.
• Intracellular receptors control gene expression by directly binding to DNA.

Ligand-Gated Ion Channels (LGICs)

• LGICs are membrane proteins that contain subunits arranged around a central pore.
• The receptor itself forms the ion channel, allowing ion flow down a concentration gradient.
• LGICs are activated by ligands, such as neurotransmitters, and operate on a timescale of milliseconds.
• Examples of LGICs include:
  • 5-HT3 receptors activated by serotonin (5-HT).
  • Nicotinic acetylcholine receptors activated by acetylcholine (ACh).
  • GABAA receptors activated by GABA.
  • AMPA, Kainate, and NMDA receptors activated by glutamate.
  • P2x Receptors activated by ATP.

Receptor Tyrosine Kinases (RTKs)

• RTKs are transmembrane receptors that signal through tyrosine phosphorylation.
• They possess an extracellular domain for ligand binding, a transmembrane helix, and an intracellular domain containing tyrosine kinase activity.
• Activated RTKs trigger a signaling cascade involving adapter proteins like Grb2, which can recruit downstream signaling molecules, such as Ras.
• The Ras protein can then activate various signaling pathways, ultimately leading to cellular responses.
• Ras acts as a molecular switch in the signaling pathway and promotes cell proliferation.

Nuclear Receptors

• Nuclear receptors are intracellular proteins that bind to hormones and regulate gene transcription.
• There are two main types:
  • Homodimeric receptors, which exist as dimers in the cytoplasm, such as estrogen, progesterone, androgen, glucocorticoid, and mineralocorticoid receptors.
  • Heterodimeric receptors that exist in the nucleus and form dimers with Retinoid X Receptor (RXR), such as receptors for thyroid hormone, retinoic acid, and vitamin D.
• Both types of nuclear receptors bind to DNA as dimers and require phosphorylation for activation.
• Homodimers bind to inverted repeats (palindromes) in DNA, while heterodimers bind to direct repeat motifs.
• The spacing between the repeat motifs determines which hormone can bind to the receptor.

Summary of Receptor Types

• Ligand-gated Ion Channels: Fast acting via ion flux.
• G-Protein Coupled Receptors: Signal via G protein activation.
• Tyrosine Kinase-linked Receptors: Signal through tyrosine phosphorylation.
• Intracellular Receptors: Signal through gene regulation.