L6 Receptors as drug targets 3

Learning Outcomes

• Classification of receptors by structure and function.
• Recognition of subfamilies within receptor families.
• Description of receptor structures in four main families.
• Understanding functions of receptors across the four families.

Overview of Receptor Classification

• Receptors can be categorized by:
  • Function: Opening ion channels, activating G-proteins, triggering enzymes, interacting with DNA.
  • Structure: Understanding protein composition and amino acid/nucleotide sequences.

Receptor Families

• Major families include:
  • Ion channel receptors
  • G-protein coupled receptors (GPCRs)
  • Intrinsic enzyme receptors
  • DNA binding receptors

Ion Channel Receptors

• Also known as ionotropic, ligand-gated, or receptor-operated ion channels.
• Types include:
  • Pentameric (e.g., GABAA, Nicotinic acetylcholine, 5-HT3)
  • Tetrameric (e.g., NMDA, AMPA, Kainate receptors)
  • Trimeric (e.g., P2X receptors)

Pentameric Ion Channels

• Pentameric ion channels are complexes formed by five subunits. These can either be homopentamers, which consist of identical subunits, or heteropentamers, composed of different types of subunits. This structural diversity allows for varying functional properties and regulatory mechanisms.

• Ligand binding for pentameric channels occurs in the extracellular space, which is crucial for channel activation. The binding of specific ligands triggers conformational changes that lead to ion flow through the channel.

• These channels allow the passage of several common ions: sodium ions (Na⁺) and calcium ions (Ca²⁺) contribute to depolarization of the membrane, while potassium ions (K⁺) and chloride ions (Cl⁻) primarily cause hyperpolarization, which is essential for returning the membrane potential to a resting state.

Tetrameric Ion Channels

• Tetrameric ion channels are made up of four subunits, which are always heteropentamers, meaning they are composed of different subunit types. This arrangement is critical for their functioning and specificity to certain ions.

• These channels consist of three transmembrane domains that encircle a central flexible pore. The design of the pore adapts according to ion type, ensuring proper ion selectivity and conductance.

• They are permeable to common ions such as sodium (Na⁺), potassium (K⁺), and sometimes calcium (Ca²⁺), contributing to various physiological processes, including muscle contraction and neurotransmission.

Trimeric Ion Channels

• Trimeric ion channels are organized into three subunits, and their structure prominently features two alpha helices, which play a crucial role in the stability and functionality of the channel.

• The architecture of these channels is primarily extracellular, which facilitates the process of depolarization as ions flow through the channel upon activation, playing key roles in signal transduction across neuronal and muscle membranes.

G-Protein Coupled Receptors (GPCRs)

• Also referred to as metabotropic, seven membrane-spanning, or serpentine receptors.
• Made up of approximately 1200 genes (3-4% of the human genome), with 67% being odorant receptors.
• Classes include:
  • Class A: Ligand binding site is in the transmembrane domain.
  • Class B: Ligand binding occurs externally, suited for large proteins.
  • Class C: Bind ligands in the extracellular domain and typically act as dimers.

Intrinsic Enzyme Receptors

• Known as pleiotropic or catalytic receptors.
• Include receptors for growth factors, cytokines, and insulin.
• Function via phosphorylation:
  • Steps: Ligand binding, dimerization, autophosphorylation, substrate phosphorylation.

DNA Binding Receptors

• Referenced as nuclear receptors or ligand-activated transcription factors, utilizing zinc fingers.
• Bind to steroid hormones, thyroid hormones, and retinoic acid.
• Activated in the cytosol and migrate to the nucleus to affect transcription.

Properties of Different Receptor Families

• Ion Channels: Multiple subunits, very fast response (µs-ms), low amplification.
• GPCRs: Single protein, fast response (ms-s), very high amplification.
• Intrinsic Enzymes: Often dimers, slow response (mins-hours), high amplification.
• DNA Binding: Dimers, very slow response (hours-days), high amplification.

Key Concepts and Terminology

• Orphan receptor: A receptor with a known structure but no identified ligand.
• Ligands for DNA binding receptors must be lipophilic to cross the plasma membrane.
• Receptor types and their mechanisms enable diverse physiological responses and signal amplification.