Question 4

College Answer

Candidates were required to synthesize knowledge across a number of areas and have a
good overview of the topic. This included the following - Insulin (acts to up-regulate Na/K 
ATPase activity promoting intracellular shift of potassium in adipose and muscle tissue); 
catecholamines (beta2 stimulation up-regulates Na/K ATPase activity promoting 
intracellular shift of potassium); aldosterone; pH (acidosis promotes H+/K+ exchange (via 
H+/K+ antiport), and reduces the activity of the Na K ATPase pump); osmolality (cellular 
dehydration increases intracellular K+ concentration promoting diffusion of potassium out 
of the cells); exercise; plasma potassium; temperature.

Discussion

Unlike most scenarios where the flux of something across a membrane is being asked about, this time it appears the examiners did not expect something brutally stupid like a rote-learned recitation of Fick's Law of diffusion. Or, at least, from a reading of their answer, one develops the impression that genuinely relevant factors were being asked about. Mechanisms governing the transcellular movement of potassium account for 90% of our medical strategies for the management of hyperkalemia, and it would have been a pity to waste that question on something like the Gibbs Donnan effect.

Anyway:

• Factors affecting Na+/K+ ATPase activity:
  • Insulin  increases the phosphorylation of the insulin receptor substrate protein (IRS-1), which leads to the activation of atypical protein kinase C and the insertion of extra Na⁺/K⁺ ATPase pumps into the membrane
  • Aldosterone increases the activity of Na⁺/K⁺ ATPase pumps in skeletal muscle (Phakdeekitcharoen et al, 2011)
  • β-agonists increase the activity of Na⁺/K⁺ ATPase pumps in skeletal muscle 
• Factors affecting ATP-sensitive K+ channels:
  • Their role is to link membrane excitability to metabolism
  • They open in the absence of ATP, decreasing the resting membrane potential
  • Found on vascular smooth muscle, cardiac muscle, skeletal muscle and pancreatic β cells
  • Affected by:
    • Glucagon (decreases ATP, increases extracellular potassium)
    • Glucose (increases ATP, drives extracellular potassium down)
    • Sulfonylureas (directly close the ATP-sensitive K channels)
    • Glibenclamide (directly closes  the ATP-senitive K channels)
• Factors involving nonspecific cation channels:
  • Eg. acetylcholine-gated sodium channels in the neuromuscular junction
  • Activation of these channels allows sodium into the cell and potassium out of the cell
  • (eg. in the context of suxamethonium use, and/or in the presence of denervation)
• Factors affecting acid-base balance:
  • Na⁺/H⁺ exchanger in skeletal muscle brings sodium into the cell
  • Sodium then acts as a substrate for Na⁺/K⁺ ATPase, increasing intracellular K⁺ uptake
  • Acidosis decreases the Na⁺/H⁺ exchange and therefore decreases the K⁺ uptake
• Factors affecting osmolality balance:
  • Hypertonic solutions (eg. mannitol, hypertonic saline) produce hyperkalemia by moving potassium out of cells by solute drag(i.e. along with osmotic movement of water)
• Unclear mechanisms:
  • Temperature change produces a transcellular shift of potassium, but the mechanism underlying this is unclear. Hypothermia produces hypokalemia. 

Rastegar, Asghar. "Serum potassium." Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition (1990).

Palmer, Biff F. "Regulation of potassium homeostasis." Clinical Journal of the American Society of Nephrology 10.6 (2015): 1050-1060.

Gumz, Michelle L., Lawrence Rabinowitz, and Charles S. Wingo. "An integrated view of potassium homeostasis." New England Journal of Medicine 373.1 (2015): 60-72.

Greenlee, Megan, et al. "Narrative review: evolving concepts in potassium homeostasis and hypokalemia." Annals of internal medicine 150.9 (2009): 619-625.

Stone, Michael S., Lisa Martyn, and Connie M. Weaver. "Potassium intake, bioavailability, hypertension, and glucose control." Nutrients 8.7 (2016): 444.