Question 4

Describe the factors that affect the flux of potassium across the cell membrane

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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.


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.


  • 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+/Hexchanger 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+/Hexchange 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.