Examkin

Question

Difficulty: MediumEndocrine and Metabolic Mechanisms

A 45-year-old woman is admitted to the hospital with central diabetes insipidus following a transsphenoidal pituitary adenoma resection. She is administered intravenous desmopressin to manage her profound polyuria and hypernatremia. Arrange the following cellular and biochemical events in the correct chronological sequence that occurs in the principal cells of the renal collecting duct following the administration of this medication.

  1. 1Binding of the medication to Gs-protein-coupled V2 receptors on the basolateral membrane
  2. 2Stimulation of adenylate cyclase and subsequent elevation of intracellular cyclic AMP (cAMP)
  3. 3Activation of protein kinase A (PKA) by elevated cAMP levels
  4. 4Phosphorylation of intracellular vesicles containing aquaporin-2 (AQP2) water channels
  5. 5Translocation and exocytosis of aquaporin-2 channels into the apical membrane

Answer

The correct sequence begins with the binding of desmopressin to the V2 receptor, followed by adenylate cyclase activation, PKA activation, aquaporin vesicle phosphorylation, and finally, apical membrane insertion.
Desmopressin is a synthetic analog of antidiuretic hormone (ADH) that specifically acts on V2 receptors located on the basolateral membrane of principal cells in the late distal tubule and collecting duct. Because V2 receptors are Gs-protein coupled, ligand binding stimulates adenylate cyclase, resulting in the conversion of ATP to cAMP. The subsequent rise in intracellular cAMP activates protein kinase A (PKA). PKA then phosphorylates regulatory proteins on intracellular vesicles containing aquaporin-2 (AQP2) water channels. This phosphorylation cascade triggers the translocation and exocytosis of these vesicles into the apical (luminal) membrane. The increased density of AQP2 channels allows free water to be passively reabsorbed down its osmotic gradient from the tubular lumen into the hyperosmolar medullary interstitium, rapidly concentrating the urine and resolving the patient's polyuria.

Step-by-Step Solution

1
Identify the medication and its specific cellular target.
Desmopressin targets V2 receptors located on the basolateral membrane of the renal collecting duct.
Establishing the correct receptor and its location is the necessary first step in signal transduction.
2
Determine the specific G-protein pathway associated with V2 receptors.
V2 receptors are Gs-coupled, leading to the activation of adenylate cyclase and increased cAMP.
Different endocrine receptors utilize different second messengers (e.g., V1 utilizes Gq/IP3, whereas V2 utilizes Gs/cAMP).
3
Trace the intracellular kinase cascade initiated by cAMP elevation.
Elevated cAMP activates Protein Kinase A (PKA), which then phosphorylates target intracellular vesicles.
To establish the biochemical link between the second messenger and the mobilization of aquaporins.
4
Identify the final cellular outcome that alters physiology.
Phosphorylated AQP2 vesicles are inserted into the apical membrane, increasing water permeability.
This completes the mechanism that allows for free water reabsorption down its osmotic gradient.

Key Concept

Cellular mechanism of action of ADH (vasopressin) and its analogs on the renal collecting duct
Rate this question

Topics

Endocrine and Metabolic Mechanisms

More questions from this topic