Receptor Types in Cell Biology

Receptor Types

• Ligand-gated Ion Channels (LGICs): These receptors are comprised of subunits surrounding a central pore. The receptor acts as the ion channel, allowing ion flow down a concentration gradient.
  • Examples: 5-HT3, nicotinic, GABAA, AMPA/Kainate/NMDA, P2X
  • Time Scale: milliseconds
  • Regulation: The desensitized state usually has higher affinity for the agonist
  • Biophysics: The physical characteristics of these channels are being further researched, with topics like the role of the lipid bilayer in ion channel function being explored.

Receptor Tyrosine Kinases (RTKs)

• Structure: RTKs have an extracellular domain for ligand binding, a single transmembrane helix, and an intracellular domain with tyrosine phosphorylation sites.
  • Example: Insulin receptor
  • Signal Transduction: Phosphorylated tyrosine residues on the intracellular domain bind adapter proteins, which in turn activate downstream signaling molecules, such as the Ras protein.
  • Ras Signaling: Activated Ras triggers various cell signaling pathways, leading to changes in protein activity and gene expression, ultimately impacting cell proliferation.

Tyrosine Kinase-Linked Receptors (TKLRs)

• Structure: Similar to RTKs in that they have tyrosine kinase domains, with variations in structure and function.
• Signal Transduction: These receptors function by activating tyrosine kinases, initiating signaling pathways leading to changes in gene expression and cellular responses.

Nuclear Receptors

• Types:
  • Homodimers: Consist of two identical subunits, found in the cytoplasm, and include receptors for estrogen, progesterone, androgen, glucocorticoids, and mineralocorticoids.
  • Heterodimers: Composed of different subunits, usually an RXR (Retinoid X Receptor) and another receptor, found in the nucleus, and include receptors for thyroid hormone, retinoic acid, vitamin D, and 9-Cis retinoic acid.
• Mechanism:
  • Homodimers: Bind to DNA as dimers, typically recognize inverted repeats (palindromes) with varying spacing between the half-sites.
  • Heterodimers: Also bind DNA as dimers, typically recognize direct repeats with varying spacing between the half-sites.
• Activation: All nuclear receptors require phosphorylation for optimal activation.

Receptor Summary

• Ligand-gated ion channels: Rapidly activate ion flow upon ligand binding.
• GPCRs: Activate G proteins to initiate signaling cascades.
• Tyrosine-kinase linked receptors: Phosphorylation of tyrosine residues on intracellular domains initiates signaling cascades.
• Intracellular receptors: Ligand binding to these receptors inside the cell directly affects gene expression through DNA binding.

Ligand-Gated Ion Channels

• Ligand-gated ion channels are membrane-bound proteins that open in response to a specific ligand binding, enabling the passage of ions across the cell membrane.
• These channels play a crucial role in rapid signalling in the nervous system and muscle cells.
• They are composed of multiple receptor subunits that form a central pore allowing ions to flow down their concentration gradient.
• The receptor itself acts as the ion channel.
• Examples of ligand-gated ion channels include:
  • 5-HT3 (serotonin receptor), nicotinic acetylcholine receptor, GABAA receptor, AMPA, Kainate, NMDA glutamate receptors, P2X purinergic receptor, muscarinic acetylcholine receptor, GABAB receptor, and mGluR glutamate receptors.
• Their signalling is rapid, occurring within milliseconds.
• They undergo desensitization, a process where continued exposure to the agonist reduces the channel's response. The desensitized state often has a higher affinity for the agonist.

Receptor Tyrosine Kinases (RTKs)

• RTKs are transmembrane receptors that play a vital role in cell growth, differentiation, and survival.
• They consist of an extracellular domain that binds to ligands, a single transmembrane helix, and an intracellular domain containing tyrosine kinase activity.
• Ligand binding to the extracellular domain triggers autophosphorylation of tyrosine residues within the intracellular domain.
• Phosphorylation creates docking sites for other signaling molecules, initiating a cascade of downstream events.
• The insulin receptor is a notable example of an RTK, although its structure is atypical.
• Another example is the epidermal growth factor receptor (EGFR), which is involved in cell proliferation and differentiation.
• Platelet-derived growth factor receptor (PDGFR) is also an important RTK involved in cell growth and wound healing.
• Growth receptor binding protein 2 (Grb2) is an adapter protein that links signaling molecules.
• Ras is a small GTPase protein that is activated by RTK signaling and plays a crucial role in cell proliferation.

Tyrosine Kinase-Linked Receptors (TKLRs)

• TKLRs share similarities with RTKs but have distinct mechanisms of action.
• They do not have intrinsic kinase activity.
• Instead, they associate with cytosolic tyrosine kinases upon ligand binding.
• These receptors exhibit significant variation in receptor:ligand stoichiometry.
• Examples of TKLRs include receptors for tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), transforming growth factor-beta (TGF-beta), and various cytokines.

Nuclear Receptors

• Nuclear receptors are intracellular proteins that regulate gene expression in response to lipid-soluble ligands.
• They are characterized by a DNA-binding domain and a ligand-binding domain.
• Nuclear receptors can be classified as:
  • Homodimers: These receptors exist as dimers of identical subunits and are located in the cytoplasm. Examples include receptors for estrogen, progesterone, androgen, glucocorticoid, and mineralocorticoid.
  • Heterodimers: These receptors form dimers with a retinoid X receptor (RXR). They are already present in the nucleus. Examples include receptors for thyroid hormone, retinoic acid (vitamin A).
• All nuclear receptors bind to DNA as dimers and require phosphorylation for activation.
• Homodimeric nuclear receptors typically bind to inverted repeat half-sites on DNA, which are palindromic sequences. The spacing between the half-sites determines the receptor's specificity.
• Heterodimeric nuclear receptors usually bind to direct repeat half-sites on DNA, and the spacing between these sites dictates their recognition.

Summary

• Ligand-gated ion channels, G-protein coupled receptors, tyrosine kinase-linked receptors and intracellular receptors each have distinct structure, function and signaling pathways.
• These receptors play crucial roles in cellular communication and diverse physiological processes.

Ligand-gated Ion Channels

• Ligand gated ion channels are comprised of receptor subunits encircling a central pore
• The receptor is also the ion channel
• Ion flow is dictated by concentration gradients
• Action occurs on a timescale of milliseconds
• examples include 5HT3, nicotinic, GABAA, AMPA, Kainate, NMDA, P2X
• The desensitized state tends to have a higher affinity for agonists

Receptor Tyrosine Kinases (RTK)

• The insulin receptor is atypical, often used as an example
• Examples of RTK receptors include epidermal growth factor receptor and platelet-derived growth factor receptor
• The extracellular domain binds to the signal ligand
• The single transmembrane helix connects the extracellular and intracellular domains
• The intracellular domain has tyrosine phosphorylation which determines the signal
• Adapter proteins are involved in signaling but do not themselves directly signal

Ras Cell Signaling

• Active Ras triggers the activation of numerous pathways
• Ras activation is essential for cell proliferation by inducing changes in protein activity and gene expression

Tyrosine Kinase-Linked Receptors

• Receptors are involved in many cellular processes, especially those involving cell differentiation and proliferation
• The stoichiometry of receptor:ligand is highly variable
• These receptors exhibit multiple variations on a theme, including different numbers of transmembrane domains
• These receptors regulate signal transduction pathways that can activate different downstream effectors and different biological functions
• Nuclear exclusion motif can be exposed or hidden to regulate nuclear localization

Nuclear Receptors

• These receptors are categorized as either homodimers or heterodimers
• Homodimeric nuclear receptors exist in the cytoplasm and include receptors for oestrogen, progesterone, androgen, glucocorticoid, and mineralocorticoid
• Heterodimeric nuclear receptors exist in the nucleus and include thyroid hormone, retinoic acid (vitamin A) receptors
• All nuclear receptors require phosphorylation for activation
• Homodimeric nuclear receptors exhibit inverted repeat half-sites as they bind to DNA
• Heterodimeric nuclear receptors bind to direct repeat half-sites
• The spacing of the recognition sites determines the structure and function of each receptor complex
• Heterodimer receptors have a common receptor monomer, RXR

Summary

• Ligand-gated ion channels, G-protein coupled receptors, tyrosine kinase-linked receptors, and intracellular receptors are all types of receptors that transduce signals in the body

Explore the different types of receptors, focusing on Ligand-gated Ion Channels and Receptor Tyrosine Kinases. Learn about their structures, functions, examples, and the biophysics behind ion channel operation. This quiz will test your understanding of key concepts in cellular signal transduction.