Physiology, Membrane


Article Author:
Tom Herrmann


Article Editor:
Sandeep Sharma


Editors In Chief:
Jasleen Jhajj
Cliff Caudill
Evan Kaufman


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
3/2/2019 10:23:18 AM

Introduction

The human cell membrane is the cornerstone of an elaborate interplay between the extracellular and the intracellular worlds. Understanding the physiology of the cell membrane provides the foundation for understanding many processes in the human body from how the heart beats to how neurons communicate, arrhythmia evolve and muscle pathology in many neurological diseases. 

Cellular

Membrane Composition

At the basic level, the cell membrane is a collection of lipid (namely phospholipid) and protein components. The phospholipid structure forms from a hydrophilic phosphorylated glycerol "head" and two hydrophobic fatty acid "tails." The cell membrane possesses a phospholipid bilayer, with the hydrophilic heads facing outwards and the hydrophobic tails facing inwards.[1] An additional lipid component is cholesterol, which prevents excessive membrane fluidity at elevated temperatures and ironically allows for membrane fluidity at decreased temperatures by preventing lipids from packing together.[2]  The protein component of the cell membrane includes either integral proteins (embedded within the membrane) and peripheral proteins (outside of the membrane).  Examples of integral proteins include any membrane channels, membrane pores, membrane receptors, and adhesion anchors.[3]  Peripheral proteins loosely attach to the outside of the cell membrane by electrostatic forces; these peripheral proteins serve multiple functions in the cell membrane including signaling, recognition, membrane trafficking, cell division, and cell structure.[4] The lipid component (phospholipids, cholesterol, and glycolipids) allows for high permeability of lipid-soluble compounds such as steroid hormones, carbon dioxide, and oxygen. These lipids also inhibit the passive diffusion of hydrophilic substances. The protein component is responsible for the transportation of hydrophilic substances such as water, glucose, and ions.

Membrane Transportation

Transport across the cell membrane takes the form of simple diffusion, facilitated diffusion, and active transport. Simple and facilitated diffusion occurs without the use of energy expenditure and is dependent on a molecule's electrochemical gradient as well as the intrinsic size and solubility of the molecule. Very small, uncharged, nonpolar substances with high lipid solubility, like oxygen and carbon dioxide, move quickly through the cell membrane via passive diffusion, while water, though small, is insoluble in lipids and thus needs to travel through a membrane channel protein to flow into the cell.  This transport through a channel protein is an example of facilitated diffusion.[5] Active transport, like facilitated diffusion, uses a protein carrier, but active transport requires energy expenditure because it must move a molecule against its electrochemical gradient.  One of the typical examples of active transport is the Na/K ATPase pump, which helps to restore a high extracellular Na and high intracellular potassium by using one ATP to pump three sodium (Na) ions extracellularly and two potassium (K) ions intracellularly.[6]

Function

Electrochemical Gradient and Resting Membrane Potential

One of the essential functions of the cell membrane is to establish an electrochemical gradient via transportation of ions.  The biggest factors in the electrochemical gradient generation are:

  • Potassium leak channels 
  • Sodium/potassium (Na/K) electrogenic pumps

The Na/K pump uses ATP to transport three Na ions extracellularly and two K ions intracellularly. This causes pooling of K intracellularly and Na extracellularly.[6] Based on natural diffusion, molecules will always travel from a high concentration to a low concentration (chemical gradient). The cell membrane contains many K "leak" channels which allow the high intracellular K to flow down its chemical gradient and deposit extracellularly.  These channels are always open and thus always "leaking" potassium out of the cell. Potassium ions have a positive charge. When K ions move from inside to the outside of the cell via its chemical gradient these positive ions deposit on the outside of the membrane creating transmembrane electrical potential with a positive charge outside of the membrane and negative charge on the inside of the membrane. This transmembrane potential creates the electrical gradient of the cell membrane in which anything with a positive charge will attempt to flow down its electrical gradient and move intracellularly.  In theory, ions will stop moving across the cell membrane when the ion's chemical gradient is equal to its electrical gradient, at this point the cell membrane is at its resting membrane potential. The cell membrane has varying levels of permeability to Na, K, and chloride (Cl) with K being the most permeable in the resting state and thus, K has the most influence on the resting membrane potential of the cell.[7]

Action Potential Generation

All cells create a resting membrane potential but neurons and muscle cells are termed "excitable" cells and can create electrical impulses called action potentials. This cellular excitability is based on specific voltage-gated channels present in the excitable cell membrane. Neurons generate action potentials mainly through the use of Na voltage-gated channels and K voltage-gated channels, while muscle cells, specifically cardiac myocytes, incorporate the use of Na, K, and Calcium (Ca) voltage-gated channels.[8]

The resting membrane potential in neurons is close to a negative 70 millivolts. In neurons, when excitatory neurotransmitters are released the resting membrane potential can be summatively depolarized and when the depolarization reaches a threshold level of approximately negative 55 millivolts, the Na-voltage gated channels open allowing a huge influx of positive Na ions to flow into the cell which creates an electrical current (the action potential), which propagates down the neural cell membrane by continually opening more and more Na-voltage gated channels. The membrane potential moves from negative seventy millivolts to positive thirty millivolts, which in turn, opens K voltage-gated channels, having the opposite (repolarizing) effect on the cell membrane returning the membrane to its natural resting membrane potential.[9] This action potential generation is the basis for all communication between neurons and the rest of the body.

Clinical Significance

Effect of Serum Potassium On Electrical Conduction

Because potassium has the most significant influence on the transmembrane potential of the cell, levels of potassium in the blood have a considerable influence on electrical activity in the heart/neurons and help to explain why a low or high level of potassium can result in weakness and heart arrhythmias.  In the heart, a high or low level of potassium changes the transmembrane potential, which in and of itself promotes cardiac arrhythmia, but also indirectly promotes cardiac arrhythmia by altering the electrical gradient of other ions, namely Na, Cl, and calcium.[10]

At muscle level, primary periodic paralysis happens due to defect in the ion channels. At the neuronal level change in mental status with or without seizure can happen due to an altered transmembrane potential which can occur due to increased or decreased levels of Na, K and Ca.

Understanding the basic physiology of the cell membrane and how ion channels control it has lead to a better understanding of so many disease processes and accordingly developing effective medical treatments for them. By altering the resting membrane, potential hypokalemia can lead to tachyarrythmias and hyperkalemia to bradyarrhythmias. For example in cases of hyperkalemia where bradyarrhythmias are very common calcium gluconate/calcium chloride can be given to stabilize the resting membrane potential.[11][12]

 Magnesium has been successfully used in severe exacerbations of asthma and in eclampsia where it alters the neuromuscular transmissions by changing calcium entry into the cellular membrane.[13]


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Physiology, Membrane - Questions

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A 61-year-old patient comes to the emergency department complaining of heart palpitations. He is found to have a cardiac arrhythmia. Electrolytes are checked, and he is found to have elevated serum sodium and decreased serum potassium. Which electrolyte level is more likely to cause his arrhythmia and why?



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A newly discovered species of mycoplasma bacteria is found to have a higher resistance to cold temperatures. What cellular property might facilitate tolerance to a colder environment?



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A large pharmaceutical company is inventing a new drug. For it to penetrate a cell membrane in the most efficient way possible, what should be the characteristics of its optimal structure?



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Physiology, Membrane - References

References

Shi Y,Cai M,Zhou L,Wang H, The structure and function of cell membranes studied by atomic force microscopy. Seminars in cell     [PubMed]
Cooper RA, Influence of increased membrane cholesterol on membrane fluidity and cell function in human red blood cells. Journal of supramolecular structure. 1978;     [PubMed]
Vit O,Petrak J, Integral membrane proteins in proteomics. How to break open the black box? Journal of proteomics. 2017 Feb 5;     [PubMed]
Whited AM,Johs A, The interactions of peripheral membrane proteins with biological membranes. Chemistry and physics of lipids. 2015 Nov;     [PubMed]
Yang L,Zhang J,Che X,Gao YQ, Simulation Studies of Protein and Small Molecule Interactions and Reaction. Methods in enzymology. 2016;     [PubMed]
Morth JP,Pedersen BP,Toustrup-Jensen MS,Sørensen TL,Petersen J,Andersen JP,Vilsen B,Nissen P, Crystal structure of the sodium-potassium pump. Nature. 2007 Dec 13;     [PubMed]
Wright SH, Generation of resting membrane potential. Advances in physiology education. 2004 Dec;     [PubMed]
Molnar P,Hickman JJ, Modeling of action potential generation in NG108-15 cells. Methods in molecular biology (Clifton, N.J.). 2014;     [PubMed]
Gao BX,Ziskind-Conhaim L, Development of ionic currents underlying changes in action potential waveforms in rat spinal motoneurons. Journal of neurophysiology. 1998 Dec;     [PubMed]
Weiss JN,Qu Z,Shivkumar K, Electrophysiology of Hypokalemia and Hyperkalemia. Circulation. Arrhythmia and electrophysiology. 2017 Mar;     [PubMed]
Castro D,Sharma S, Hypokalemia . 2018 Jan     [PubMed]
Simon LV,Farrell MW, Hyperkalemia . 2018 Jan     [PubMed]
Allen MJ,Sharma S, Magnesium . 2018 Jan     [PubMed]

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