study questions 13 and 14

Study Questions NPB 130, Autumn 2025 Lecture 13 and 14: HPA and Stress

General Overview of the HPA Axis and POMC

  • POMC (Proopiomelanocortin)
    • Definition: A precursor polypeptide that can be cleaved into several active peptides involved in stress responses.
    • Role in HPA Axis: Serves as a source of ACTH (Adrenocorticotropic hormone) and other peptides.
    • Location of Production: Synthesized in the anterior pituitary gland.
    • Post-Translational Processing:
    • Involves cleavage by various enzymes to produce ACTH and other hormones like beta-endorphins.
    • This conversion is crucial for the biological activity of the final products.

ACTH Synthesis and Function

  • ACTH (Adrenocorticotropic Hormone)
    • Synthesis:
    • No single “gene for” ACTH, instead, it is produced from the cleavage of POMC.
    • Specific enzymes cleave POMC to produce ACTH in the pars distalis of the anterior pituitary.
  • Function: Stimulates the adrenal cortex to produce cortisol and other steroid hormones.

Steroid Biosynthesis Process in Adrenal Cortex

  • Roles of Elements in Steroid Biosynthesis:
    1. ACTH: Stimulates steroidogenesis; qualifies as “short-term” effect due to immediate response.
    2. GPCR (G Protein-Coupled Receptors): Binds ACTH; initiates signaling cascade; short-term effect.
    3. Adenylate Cyclase: Converts ATP to cAMP; short-term effect in transduction of hormonal signals.
    4. cAMP: Acts as a secondary messenger; induces activation of PKA; short-term effect.
    5. Activated PKA (Protein Kinase A): Phosphorylates target proteins; short-term effect, crucial for immediate responses.
    6. LDL (Low-Density Lipoprotein): Source of cholesterol; needed for steroid synthesis; long-term effect due to storage nature.
    7. LDL Receptor: Mediates uptake of LDL in adrenal cells; long-term effect through cholesterol availability.
    8. CHO Esterase: Enzyme that liberates free cholesterol from esters; long-term effect on substrate availability.
    9. StAR Protein (Steroidogenic Acute Regulatory Protein): Facilitates transport of cholesterol into mitochondria; short-term effect.
    10. p450scc (Cholesterol Side-Chain Cleavage Enzyme): Converts cholesterol to pregnenolone; short-term effect crucial for steroidogenesis.
    11. Activated CREB (cAMP Response Element-Binding Protein): Regulates gene transcription; involved in long-term effects like production of enzymes.
    12. New Protein Synthesis: Essential for producing enzymes like PEPCK; qualifies as long-term effects as changes take time.

Effects of p450scc Enzyme Absence

  • Consequences of Missing/Disabled p450scc in Different Zones of Adrenal Cortex:
    1. Zona Glomerulosa: Impaired mineralocorticoid production (e.g., aldosterone); affects sodium and fluid balance.
    2. Zona Fasciculata: Decreased glucocorticoid production (e.g., cortisol); impacts stress response and metabolism.
    3. Zona Reticularis: Reduced production of adrenal androgens; affects secondary sexual characteristics and behavior.

Location and Production of Pregnenolone

  • Location of p450scc: Found in the inner mitochondrial membrane of adrenal cortex cells.
  • Pregnenolone Appearance: First appears in the mitochondria post cholesterol conversion, initiating steroidogenesis.

Mechanism of Action of Glucocorticoids

  • Main Mechanism: Glucocorticoids like cortisol exert their effects primarily by binding to glucocorticoid receptors (GRs) in target cells, leading to altered gene expression.
  • HSP (Heat Shock Proteins):
    • Definition: Molecular chaperones that assist in proper protein folding and function.
    • Role: Help stabilize the receptor and maintain its proper configuration for binding and function.
  • GRE (Glucocorticoid Response Element): Specific DNA sequence in target genes that glucocorticoids bind to induce transcription; glucocorticoids enhance gene expression through interaction with GREs.

Time Scales of Glucocorticoid Negative Feedback on HPA Axis

  • Three Time Scales:
    1. Rapid Feedback: Minutes to hours; mediated by neurotransmitter receptors affecting pituitary secretion directly.
    2. Intermediate Feedback: Hours to days; involves GRs affecting ACTH synthesis in the anterior pituitary.
    3. Long-term Feedback: Days to weeks; GRs in the hypothalamus influence corticotropin-releasing hormone (CRH) release.

Experimental Use of Dexamethasone

  • Dexamethasone (DEX): A synthetic glucocorticoid used to study the mechanisms behind glucocorticoid feedback.
  • Findings: Demonstrates that glucocorticoids may exert effects both genomically and through non-genomic pathways such as membrane-bound receptors.

Defining Stress

  • Scenario Analysis: Wild male Arctic ground squirrels during reproductive activity post-hibernation face several stressors:
    1. Threat to Homeostasis: The demands may disrupt physiological stability, thus defined as stressful.
    2. Arousal-Aversion-Control: Behavioral responses highlight arousal and aversion, indicating stress.
    3. Physiological Response: Activation of sympathetic and HPA responses signifies stress presence, validating definitions.

General Adaptation Syndrome (GAS)

  • Three Phases of GAS:
    1. Alarm Phase: Immediate response; sympathetic nervous system predominates.
    2. Resistance Phase: Adaptation and coping; HPA axis response counteracts stressors and glucocorticoids mediate this phase.
    3. Exhaustion Phase: Prolonged stress leading to depletion of resources; both systems can be affected, leading to health issues.

Gluconeogenesis and Glucocorticoids

  • Gluconeogenesis: The process leading to glucose production from non-carbohydrate substrates notably in the liver during stress.
    • Tissues Involved: The primary substrates come from muscles (amino acids) and other organs such as kidneys; the liver performs gluconeogenesis.
    • Substrates Utilized: Lactate, glycerol, and alanine are key substrates used in this metabolic process.
  • Enzymes: PEPCK and Glucose-6-Phosphatase:
    • PEPCK (Phosphoenolpyruvate carboxykinase): Catalyzes a critical step in gluconeogenesis; glucocorticoids increase PEPCK expression to enhance glucose production.
    • Glucose-6-Phosphatase: Critical for converting glucose-6-phosphate to glucose; elevated glucocorticoids upregulate its activity to support gluconeogenesis.

Glucocorticoid Effects on Liver Metabolism

  • Glucocorticoids: Produce complex effects on liver metabolism;
    1. Glucose Production: Increase gluconeogenesis to provide energy during stress.
    2. Glycogen Synthesis: Paradoxically decrease glycogen synthesis; elevated CORT reduces glycogen storage through inhibition of key enzymes (e.g., glycogen synthase) which aligns with increased energy availability aims.

Glucocorticoid Receptor Location

  • Body Receptors for Glucocorticoids: Receptors are widely distributed in tissues including the liver, muscle, and brain.

Food Caching Behavior in Mountain Chickadees

  • Food Caching: The behavior where birds store food for later use; essential for survival through variable energy demands, crucial during harsh winter conditions.

Glucocorticoid Secretion Curves

  • Glucocorticoid Secretion During Stress:
    • Sketch the generalized curve depicting increased glucocorticoid levels during prolonged stress and overlay the simulated stress response observed in mountain chickadees study.

The Impact of Elevated Corticosterone on Mountain Chickadees

  • Effects on Behavior:
    1. Food Consumption: Experimental elevation leads to changes in foraging behavior and food caching practices.
    2. Spatial Memory Tasks: Elevated glucocorticoids affect performance; analysis required to determine memory retention versus motivation.
  • Researchers' Rationale: Understanding changes in hippocampal structure could provide insights into the link between physiological stress responses and cognitive functions.
  • Hippocampal Analysis: Comparison of volumes, neuronal numbers, and cell division rates between CORT-implanted and controls to assess neuroplastic effects due to stress exposure.

Congenital Adrenal Hyperplasia and p450c21 Deficiency

  • p450c21 Enzyme Deficiency: Leads to reduced glucocorticoid production and consequentially increased ACTH release due to lack of negative feedback.
    1. Fetal Glucocorticoid Production: Impaired during development; affects fetal stress response.
    2. ACTH Production: Elevated levels due to deficiency; leads to hyperplasia of adrenal glands.
  • Adrenal Androgen Production: Increased due to unregulated ACTH activity, impacting reproductive development and functions.

Anti-Inflammatory Effects of Glucocorticoids

  • Mechanisms of Action: Inhibit inflammatory responses through complex interactions, with glucocorticoids presumed most effective as seen against NSAIDs.
  • Long-term Treatment Considerations: Chronic glucocorticoid use can induce feedback mechanisms systemically affecting individual physiology, which modifies treatment choices even in cases of chronic inflammation.