Hydrophilic Receptors and GPCRs Overview

Hydrophilic Receptors

• Hydrophilic signaling molecules cannot pass through the cell membrane
• Most bind to the ligand binding domain of extracellular receptors
• The intracellular domain of the receptor performs the response
• G protein-coupled receptors (GPCRs) are the largest category of cell surface receptors.

G Protein-Coupled Receptors (GPCRs)

• Important for animal sensory systems
• Span the membrane 7 times as alpha helices
• Contain a G protein that can bind to GTP or GDP
• Ligand binding changes the shape of the cytoplasmic side, activating the GPCR and G protein.
• GDP in the alpha subunit is replaced with GTP.
• The activated alpha subunit detaches from beta and gamma subunits and regulates target proteins, activating secondary messengers.

Secondary Messengers

• Amplify the signal inside the cell.
• Activate enzymes, which further amplify the signal and lead to a cellular response.
• GTP is hydrolyzed to GDP, returning the system to its resting state.

Epinephrine Example

• Binds to a specific GPCR
• Activates the GPCR
• Leads to the exchange of GDP for GTP in the alpha subunit
• The alpha subunit detaches and binds to adenylate cyclase
• Adenylate cyclase converts ATP to cAMP.
• cAMP acts as a secondary messenger and amplifies the signal, leading to the breakdown of glycogen to glucose.

Ligand-Gated Ion Channels

• Located in the plasma membrane
• Serve as gates for ions
• Ligand binding opens or closes the gate, allowing specific ions to diffuse across the membrane
• Initiate events that lead to cellular responses
• Example: Sodium-potassium pump

Receptor Protein Kinases

• Important in growth factors
• Contain both an extracellular ligand-binding domain and an intracellular kinase domain
• Ligand binding activates the kinase domain.
• Kinases transfer a phosphate group from ATP to proteins, altering the shape of the protein and triggering a response

Receptor Tyrosine Kinase (RTK)

• Two RTKs bind to the signal and dimerize (cross-linked dimer)
• Cross phosphorylation occurs, where one tyrosine residue on one RTK is phosphorylated by the kinase domain of the other RTK.
• ATP is converted to ADP to provide the phosphate group for phosphorylation.
• Phosphorylated tyrosines serve as binding sites for other proteins, initiating downstream signaling pathways.

Hydrophobic Receptors

• Internal receptor proteins
• Cause changes in gene expression
• Examples: Hormones

Agonists and Antagonists

• Agonists: Ligands that bind to receptors and cause a response (e.g., albuterol acting like adrenaline to widen airways)
• Antagonists: Ligands that bind to receptors but do not activate them (e.g., blockers)

Homeostatic Imbalances

• Genetic disorders
• Drug or alcohol abuse
• Extreme environmental conditions (heat or cold)
• Diseases: When the body cannot maintain homeostasis
  • Cancer: Uncontrolled cell growth
  • Diabetes: Inability to regulate blood glucose levels.
    • Type I: Lack of insulin production
    • Type II: Insulin resistance

Positive Feedback Loop

• Example: In childbirth, oxytocin stimulates stronger uterine contractions, creating a positive feedback loop that intensifies until birth.

Feedback Loop Failures and Disease

• Hyperglycemia in Diabetes: When insulin feedback fails, glucose levels remain high. Chronic hyperglycemia can damage tissues and organs.

Cell Signaling and Homeostasis

• Cells in a multicellular organism communicate to maintain homeostasis.
• Communication occurs through signal transduction pathways.

Cell Cycle (Prokaryotes)

• Prokaryotes reproduce asexually via binary fission.
• Steps:
  • Growth: Prokaryote grows to a sufficient size.
  • DNA Replication: DNA is copied.
  • Attachment: Circular DNA attaches to proteins on the inner cell membrane.
  • Separation: Attachment sites move apart as the cell continues growing.
  • Division: New cell membrane and cell wall are synthesized at the midpoint, forming two daughter cells.

Cell Cycle

• The life of a cell from formation to division
• Essential for reproduction, growth, and tissue repair.
• Reasons for division: Maintaining a favorable surface area to volume ratio.

Stages of the Cell Cycle

• Interphase: The longest stage (90%)
  • G1 Phase: Cell grows and performs normal functions, preparing for DNA replication.
  • S Phase: DNA replication and chromosome duplication occur.
  • G2 Phase: Final growth and preparation for mitosis.
• M Phase: Nuclear and cytoplasmic division
  • Mitosis: Nuclear division
  • Cytokinesis: Cytoplasmic division

Mitosis

• Produces two identical diploid daughter cells
• Steps:
  • Prophase: Chromatin condenses, nucleoli disappear, nuclear membrane dissolves, mitotic spindle forms, and centrosomes move apart.
  • Prometaphase: Nuclear envelope fragments, microtubules attach to kinetochores on chromosomes.
  • Metaphase: Chromosomes align at the metaphase plate.
  • Anaphase: Sister chromatids separate and move to opposite poles of the cell by microtubule shortening.
  • Telophase: Nuclear membrane reforms, chromosomes decondense.

Cytokinesis

• Cytoplasm divides, producing two daughter cells.

Cell Cycle Checkpoints

• G1 Checkpoint: Checks for DNA damage, adequate growth, and enough resources.
• G2 Checkpoint: Checks for successful DNA replication and cell size.
• M Checkpoint: (Spindle Checkpoint) Ensures that chromosomes are properly attached to microtubules.

Tumor Suppressor Genes

• Help cells regulate cell division
• A mutation in one allele of a tumor suppressor gene does not necessarily cause cancer, as the other allele can still function.
• Mutations in tumor suppressor genes can cause cancer cells to bypass checkpoints and divide uncontrollably.

External Cell Cycle Regulators

• Growth Factors: Hormones that stimulate cell growth.
• Contact (or Density) Inhibition: Cells stop dividing when they come in contact with other cells.
• Anchorage Dependence: Cells must be attached to a surface to divide.

Cancer

• Normal cells become cancerous due to DNA mutations.
• These mutations can affect genes that regulate cell growth.
• DNA damage, such as exposure to radiation, activates protein kinases that phosphorylate p53.
• p53 can help the cell repair DNA damage or trigger apoptosis.
• Mutations in p53 allow damaged cells to bypass checkpoints and divide uncontrollably.

Normal Cells vs. Cancer Cells

• Normal cells: Follow checkpoints and divide a limited number of times in culture.
• Cancer cells: Bypass checkpoints, can divide infinitely in culture, and evade apoptosis.

Tumors

• Uncontrolled growth of cancer cells can lead to a tumor.
• Benign tumors: Abnormal, but not cancerous, and do not spread.
• Malignant tumors: Cancerous, with the ability to invade surrounding tissues and metastasize (spread to other parts of the body).

Explore the intricacies of hydrophilic signaling molecules and G protein-coupled receptors (GPCRs) in this quiz. Learn how these receptors function at the cellular level, including their structure and role in amplifying signals through secondary messengers. Test your knowledge on key concepts and mechanisms involved in cellular signaling.