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The sea inside your skull - ion homeostasis

Previous posts have covered a number of the low-level building blocks that are used by cells in the brain - things like ion channels, neurotransmitters, receptors, clathrin, vesicles, etc. This post focuses on some important pieces of infrastructure that are needed to enable the brain to do its thing. 

Neurons operate in an aqueous medium - a kind of salt water bath, water that is full of postively charged ions (cations like sodium, potassium and calcium) and negatively charged ions (anions like chlorine).   Water molecules are V shaped and have a non-uniform distribution of charge - i.e. one end of the water molecule is more positively charged than the other end.  Like charges repel and unlike charges attract.  As a result, a sphere of these 'polar' water molecules tends to surround the ions (a 'sphere of hydration').   Complicating the picture further is the fact that charged particles like ions are influenced by both concentration gradients (ions flow to the region with the lower concentration of that ion) and electrical gradients (electro-magnetic fields, charge distribution)

The resting nerve has mostly Na+ on the outside of the membrane and K+ and negatively charged, non-diffusible protein on the inside. Because there is a little leakage of K+ to the outside (K+ is more permeable than Na+), the net membrane charge is positive on the outside and negative on the inside.  (Ref.: PLASMA MEMBRANE AND MEMBRANE POTENTIAL IN THE NERVE CELL - U. of Colorado)

At rest, in the absence of action potentials or any other activity, the inside of a neuron has a voltage of about -65mV compared to the outside. Neural signals are changes in this resting potential. (Ref.: Neuronal Membrane at Rest: Ionic Basis of the Membrane Resting Potential)

The resting potential results from the establishment of ionic gradients across the cell membrane for potassium, sodium, chloride, and calcium. Most membranes are permeable principally to potassium and sodium. The diffusion pressure for each ion is balanced by an electrical force from the voltage that develops across the membrane. The voltage that exactly balances each ion is the equilibrium potential for that ion. The resting potential is a weighted average of the equilibrium potentials for the ions to which the membrane is permeable. The net driving force on a given ion is the difference between the membrane potential and its equilibrium potential. (ref.

The above references get into the key equations that govern ionic behaviour: the Nernst Equation calculates the numerical value of the equilibrium potential, and the Goldman Equation calculates the membrane potential as a weighted average of the equilibrium potentials.  Not going into these here :)  

From the above, you can see that membranes are REALLY important. You need a membrane to separate two different environments with different characteristics in order to do any 'work'. Stuart Kauffman has some very interesting perspectives on this -  I've added a new NanoBiologyNotes blog entry on Membranes that touches on these ideas.  

Most neurons are interconnected indirectly with each other.   An electrical 'action potential' flows down a neuron's axon until it reaches a terminating 'bouton'  - a bulb containing mitochondria and tiny bubbles called vesicles that are filled with one or more kinds of neurotransmitters.  The action potential causes the vesicles to fuse with the axon's membrane and releaseits payload of neurotransmitters into the synaptic gap that seperates it from another neuron's dendrites or soma. (We'll call this second neuron the 'receiving neuron'). These neurotransmitters bond with ion channels in the membrane of the receiving neuron, causing a conformational change in the shape of each of the ion channels which allows ions that are present in the fluid surrounding the neurons to flow into the receiving neuron, or ions that are inside of the neuron to flow out, depending on the type of ion channel that has been opened. A single neuron can have tens of thousands of these types of indirect connections with other neurons. If enough sending neurons trigger at rougly the same time, a large enough number of ion channels in the receiving neuron will be open that the ionic concentration of the receiving neuron will hit a threshold that initiates one or more action potentials to rush through the receiving neuron to it's axon. Roughly speaking.

But, uh, where do all of these ions come from?  What establishes and maintains the correct concentration of ions outside of the neurons??

This simple question led me into some fascinating stuff on morphobiology, ph and H+ gradients, genetic toolkits and so much interesting material I'm starting up another blog to focus on it.  But, back to the original question...what's up with the ions?

Zhi-Qi Xiong and Janet L. Stringfer (Baylor College of Medicine) published a nice introduction to what is going on to establish the right environment in the brain for neurons to work in the Journal of Neurophsiology (ref.) (I've removed the references from the text to improve readability - please see the original for these):

  • Neuronal activity is associated with a rise in the extracellular potassium concentration ([K+]o) caused by efflux of potassium during action potential repolarization. Neuronal activity, in the absence of clearance mechanisms, would cause the [K+]o to rise in seconds to values that would abolish all electrical activity. However, it is known that during intense evoked neuronal activity or spontaneous epileptiform activity in the cortex  and hippocampus  [K+]o rises to a ceiling level of 10-12 mM from a resting level of 3 mM. The occurrence of a plateau, or ceiling, level during continued neuronal activity suggests that [K+]o is actively cleared from the extracellular space.

    Clearing of excess [K+]o is believed to occur by diffusion, active uptake by neurons and glia, or passive uptake by glia. There is evidence that the rate of potassium release during repetitive neuronal activity is faster than the rate at which it would diffuse away. Although neurons can take up potassium, uptake by astrocytes is believed to play a major role in regulation of [K+]o. Glia are thought to be required for the normal fine tuning of [K+]o and for the recovery of pathologically elevated [K+]o. Glia have been shown to increase their internal potassium concentration when [K+]o is increased and release it once the [K+]o decreases. They are also believed to remove potassium by spatial buffering through the glial syncytium. According to the spatial buffering hypothesis, potassium released from active neurons enters glial cells, possibly through inwardly rectifying potassium channels. Potassium is then redistributed through the network of glial cells and leaves at sites of low [K+]o. Spatial buffering can be directly demonstrated in the drone retina as a result of a fortunate spatial arrangement of neuronal and glial structures. However, the exact role of glial spatial buffering in other parts of the brain and during times when the regulation systems are significantly stressed (i.e., during synchronous epileptiform activity) is not clear. It has been argued that spatial buffering has no role in situations of elevated [K+]o.

    There's a nicely written article (Astrocytes) by Pierre J. Magistretti and Bruce R. Ransom that provides a good overview of the role played by glial cells:

    • The astrocyte is a ubiquitous type of glial cell that is defined in part by what it lacks: axons, action potentials, and synaptic potentials. Astrocytes greatly outnumber neurons, often 10:1 and occupy 25% to 50% of brain volume (1–3). Although these cells are anatomically obvious, their functions have been difficult to determine. Discoveries in the last 25 years, however, have revealed some of their functions and established the essential nature of interactions between neurons and astrocytes for normal brain function.
    • One of the best-established functions of astrocytes is regulation of brain [K]o. Astrocytes are also likely to participate in the regulation of extracellular pH. 
    • Neural activity can rapidly increase [K]o, which is tightly regulated to a resting level of about 3 mM (25). A single action potential increases the instantaneous [K]o by0.75mM(26). The increase in [K]o is proportional to the intensity of neural activity but has a so-called ‘‘ceiling’’ level of accumulation of 10 to 12 mM (27,28), which is only exceeded under pathologic conditions (29). If diffusion alone were responsible for dissipating K released from neurons, it is easily calculated that extracellular K accumulation would exceed 10 mM during normal neural activity, whereas measured increases in [K]o are in the range of 1 to 3mMindicating powerful control mechanisms (30). Homeostatic control of [K]o is needed because brain [K]o can influence transmitter release (31), cerebral blood flow (32), ECS volume (33,34), glucose metabolism (35), and neuronal activity (36). Unchecked increases in [K]o act as an unstable positive feedback loop increasing excitability.
    • Astrocytes expedite the removal of evoked increases in [K]o and limit its accumulation to a maximum level of 10 to 12mM, the ceiling level seen with intense activity such as epileptic discharge (37,38). Neurons, and perhaps blood vessels, also participate in [K]o regulation, but glial mechanisms are probably most important. Two general mechanisms of astrocyte K removal have been proposed
      (39): 1) net K uptake into astrocytes (by transport mechanisms and/or Donnan forces) and 2) K redistribution through astrocytes, which is known as K spatial buffering. The relative importance of these two mechanisms of [K]o regulation remains an open question and may depend on the nature of the [K]o increase as well as brain region (38). If glial cells take up K during neural activity and release it thereafter, a transient increase in glial [K]i should result. Astrocyte [K]i does transiently increase during neural activity and has a similar time course to the K lost from active neurons and the increase in [K]o, indicating that the K released from neurons is passing by way of the ECS into glial cells (40–42). Uptake of K into glial cells depends on the glial Na pump (38,42–44), an anion transporter that cotransports K and Na with Cl (43) and Donnan forces that propel KCl into glial cells in the face of elevated [K]o (42) (Fig 10.1). It has not been determined with certainty which of these mechanisms is quantitatively most important for K uptake. The astrocyte Na pump, however, is exquisitely sensitive to elevations of [K]o. Even a 1 mM increase in [K]o activates the Na pump in these cells indicating, perhaps, that this is the major mechanism of K sequestration (44). Neurons, of course, must eventually reaccumulate K lost during activity using their Na pump, but only glial cells show net accumulation
      of K (Fig. 10.1). It is interesting to note that the neuronal Na pump is not sensitive to small increases in [K]o and is probably activated mainly by increases in intracellular [Na] (45).

    Another key mechanism that plays an important role in regulating the ionic concentrations is something called the "Na+-K+-Cl- cotransporter" (ref.)

    • Little is known regarding how Na+-K+-Cl- cotransporter activity is regulated in the CNS. Glutamate, N-methyl-d-aspartate, and the metabotropic glutamate receptor agonist t-ACPD significantly stimulate cotransporter activity in neurons (Sun and Murali, 1998, 1999). Cotransporter activity in cortical neurons and astrocytes is elevated when intracellular Ca++ increases in the presence of high [K+]o(Schomberg et al., 2001; Su et al., 2000). Because both high [K+]o and elevated extracellular glutamate play important roles in ischemic cell damage, the authors hypothesize that stimulation of the cotransporter in neurons may contribute to overload of intracellular Na+ and Cl- and cell swelling during ischemia. Several studies suggest that the Na+-K+-Cl- cotransporter may be involved in ischemic cerebral cell damage. Twenty-four hours of hypoxia decreases cellular adenosine triphosphate (ATP) content and reduces Na+-K+-ATPase activity, while significantly increasing the Na+-K+-Cl- cotransporter activity in rat brain capillary endothelial cells (Kawai et al., 1996). Significant reduction of brain edema by the Na+-K+-Cl- cotransporter and Cl- channel inhibitor torasemide or its derivative also has been observed in focal cerebral ischemia and traumatic brain injury (Staub et al., 1994; Le Bars et al., 1996). However, no study has yet directly demonstrated a role of the cotransporter in ischemic neuronal damage.

    The ion pump Na+/K+-ATPase is a third key mechanism:

    • ref. These findings suggest that potassium redistribution by glia only plays a minor role in the regulation of [K+]o in this model. The major regulator of [K+]o in this model appears to be uptake via a Na+/K+-ATPase, most likely neuronal.


    And the Blood-brain barrier is also important, since it limits the movement of potassium through the walls of brain capillaries (more info here.)






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