Foundations · Year 1 · from Foundations
Case 1: Pheochromocytoma (G-Protein and cAMP Signaling)
Clinical Image
Source: Radiopaedia - Pheochromocytoma - CC BY-NC-SA 3.0
Case Presentation
A 42-year-old woman presents with episodes of severe headache, palpitations, and diaphoresis occurring several times weekly. During episodes, her blood pressure is markedly elevated (220/120 mmHg). Between episodes, her blood pressure is normal. Physical examination during an episode reveals tachycardia, pallor, and tremor. 24-hour urine collection shows markedly elevated catecholamines and metanephrines. CT abdomen reveals a 4 cm right adrenal mass. She is diagnosed with pheochromocytoma. Before surgical resection, she requires alpha-adrenergic blockade (phenoxybenzamine) followed by beta-blockade (propranolol) to control hypertensive crises and prevent perioperative cardiovascular complications. The pathophysiology involves excessive catecholamine (epinephrine and norepinephrine) release from the adrenal medulla tumor. These catecholamines bind to adrenergic receptors (GPCRs), activating downstream signaling. Beta-receptors couple to Gs, activating adenylyl cyclase and increasing cAMP, which activates PKA and produces cardiac effects (increased rate and contractility). Alpha-1 receptors couple to Gq, activating phospholipase C to generate IP3 and DAG, causing calcium release and vasoconstriction. Surgical resection is curative. She is screened for hereditary syndromes (MEN2, VHL, SDH mutations) given approximately 40% of pheochromocytomas have genetic predisposition.
Key Learning Points
- Catecholamines signal through GPCRs: beta-adrenergic receptors couple to Gs and cAMP/PKA pathway (cardiac effects), while alpha-1 receptors couple to Gq and PLC/IP3/calcium pathway (vasoconstriction)
- Beta-blockers (propranolol, metoprolol) are competitive antagonists at beta-adrenergic receptors, one of the most successful drug classes developed from understanding GPCR signaling
- Alpha-blockade must precede beta-blockade in pheochromocytoma to avoid unopposed alpha-mediated vasoconstriction and hypertensive crisis