hypercalcemia question

The way I have to think about it is that Ca has a stabilizing/sedative effect on neuromuscular transmission so HYPOcalcemia leads to increased excitability (twitching, spasms, tetany) while HYPERcalcemia causes decreased excitability (muscle weakness and muscle fatigue).

Hope that helps a little bit.

Amanda

Hello biochem smarties......

I have a question for you guys to ponder:

HYPERcalcemia s/sx: fatigue, lethargy, muscle weakness.

HYPOcalcemia s/sx are muscle cramps, paresthesia, tetany (+ trousseau/Chovstek signs).

I know that Ca is necessary for nerve conduction leading to muscle movement/contraction and tone (and it has other functions). If there is too MUCH Ca present, why are the s/sx that of what you would expect of hypocalcemia? I would expect to have muscle movement problems without enough Ca because why is it present with high ca levels?

thanks for any/all explanations, thoughts, theories.

There is more to it than this, but here is a somewhat simplified explanation. (While I will just talk about cardiac muscle, it can also be applied to skeletal muscle, for the most part).

There is a resting membrane potential across plasma membranes of excitable tissues (skeletal muscle, cardiac muscle, nerves). We will use cardiac muscle as an example. Normal resting membrane potential of ventricular cardiac muscle is -90mV, and the normal threshold is -60mV. The threshold is what you have to get to in order for the cell to depolarize. It is an all or nothing principle - you either depolarize or you don't. If you get to the threshold, you depolarize. If you don't get to the threshold, you don't depolarize. Calcium alters the threshold.

Too much calcium will cause the threshold potential to shift away from the resting membrane potential (therefore, the threshold potential becomes less negative). Cells are less excitable because it is now more difficult for it to get to this threshold. Hypothetically, if the threshold is normally -60mV, but now we have too much calcium on board, our threshold is now -50mv. That is a difference of 40mV that the cell has to account for in order to depolarize. In skeletal muscle, this can cause weakness, fatigue, etc.

Too little calcium will cause the threshold to become more negative (gets closer to the resting membrane potential). Therefore, it requires less to depolarize, and it is more excitable. Hypothetically, the threshold is normally -60mV, but now that we are hypocalcemic, our threshold could now be -70mV. Now there is a difference of only 20mV that the cell has to account for in order to depolarize. The diffusion of calcium into the cell is what maintains depolarization - and when you don't have as much calcium, it will take longer for the calcium to diffuse in the appropriate amounts, causing a longer depolarization. In skeletal muscle, this can cause tetany, cramps, etc. Hypocalcemia can be particularly of interest to us because of the possibility of airway muscle spasms.

Hope this helped.

I remembered from physiology that Calcium has a direct effect on sodium channels, which like heartICU said, affects the threshold. I had to cheat and refer to guyton to get the exact mechanism. This may help further explain why Hypocalcemia produces tetany, etc.

"The concentration of calcium ions in the extracellular fluid also has a profound effect on the voltage level at which the sodium channels become activated. When there is a deficit of calcium ions, the sodium channels become activated by very little increase of the membrane potential from its normal very negative level. Therefore, the nerve fiber becomes highly excitable, sometimes discharging repetitively without provocation rather than remaining in the resting state. In fact, the calcium ion concentration needs to fall only 50% below normal before spontaneous discharge occurs in some peripheral nerves, often causing muscle 'tetany.' this sometimes can be lethal because of tetanic contraction of respiratory muscles.

The probable way in which calcium ions affect the sodium channels is as follows: These ions appear to bind to the exterior surfaces of the sodium channel protein molecule. The positive charges of these calcium ions in turn alter the electrical state of the channel protein itself, in this way altering the voltage level required to open the sodium gate."

heart and focker -- awesome explanations. I can memorize the s/sx of hypo/hyperCa, but I really want to understand WHY and you nailed it.

thanks

LifeLONGstudent

Thanks, guys!

"HeartICU", you're mostly correct. Increasing extra or intra cellular concentrations of ions doesn't change action potential thresholds. AP thresholds don't change; at least not due to quantitative changes of ion presence or absence. In the case of hypercalcemia, the resting membrane potential would be hyperpolarized (made more negative in this case), drawing the membrane potential away from the AP threhold, NOT lowering the cell's AP threshold away from an absolute membrane potential. You are absolutely correct that this makes the cell "less excitable" (although it would be better to say that it requires a greater depolarizing stimulus than calling it "less excitable"; this is a semantical point that my fellow scientists and i are always arguing about; just what we need to defeat that nerd stigma, huh? ) as it requires a more intense depolarizing stimulus to reach the Action Potential threshold and initiate cellular action: nerve impulse, muscle contraction, rhythmic signal, whatever...

To numerically display it. Most excitable mammalian cells under normal homeostatic have a resting membrane potential of -70mV and action potential threshold of -55mV. (Please note that i said most, not all.) In a state of hypercalcemia, the excessive extracellular positive charge brought about by the above normal presence of calcium (2+ ionic charge) would increase the gradient between the interior and exterior of the cell. This would change the resting membrane potential to, for example, -80 mV. In the homeostatic case you only have a 15 mV bridge to gap in order to reach threshold and ellicit an action potential. But in the hypercalcemic case you now require a stronger depolarizing, 25 mV, stimulus to initiate the Action Potential.

Focker has the right answer.

Let me try to simplify though.

No matter if cardiac or skeletal muscles, contractions requires the (fast)sodium voltage gated channels opening first.

Ca++ binds to these channels.

If too little Ca++ binds, it is easier to cause a conformational change to open these channels = hyperexcitable.

If too much Ca++ binds, it is harder to cause these change = hypo-excitable.

Change in Ca++ does not affect the resting membrane potential(RMP). It only affects the threshold potential (TP). Resting membrane potential is only changed and maintained by potassium.

This is why you give calcium to a hyperkalemic pt during a code.

The hyerkalemia will increase the threshold potential, and in order to compensate calcium is given to increase the threshold potential to make the heart less excitable.

Volatile,

Ca++ does not bind to Potassium channels receptors, in this case of this discussion at least. in the focus of this discussion it is the opening of Ca++ channels that causes activation of the membrane by the ability of Calcium to flow through the opened channel thus causing depolarization of the membrane and subsequent activation of the cell. YOu are right that this is indeed dependent on/influenced by Potassium channel activation/Potassium gradient flow.

quanitative presense (or absence) has nothing to do with a membrane receptors ability to make "it is easier to cause a conformational change to open these channels". activation of the channel, ie-your "conformational change" is based solely on the presense of an agonist or strong voltage change to initiate the receptors operation. the quanitative involvement has to do with the number of receptors that are activated and the amount of Ca++ present to flow down the channel to cause a voltage change in order to overcome the Activation Potential and fire the cell. WIthout adequate Calcium there will be insufficient or no gradient and Calcium will not "flow" and thus will not create the necessary action potential to cause the cell to fire.

Volatile,

Ca++ does not bind to Potassium channels receptors, in this case of this discussion at least. in the focus of this discussion it is the opening of Ca++ channels that causes activation of the membrane by the ability of Calcium to flow through the opened channel thus causing depolarization of the membrane and subsequent activation of the cell. YOu are right that this is indeed dependent on/influenced by Potassium channel activation/Potassium gradient flow.

quanitative presense (or absence) has nothing to do with a membrane receptors ability to make "it is easier to cause a conformational change to open these channels". activation of the channel, ie-your "conformational change" is based solely on the presense of an agonist or strong voltage change to initiate the receptors operation. the quanitative involvement has to do with the number of receptors that are activated and the amount of Ca++ present to flow down the channel to cause a voltage change in order to overcome the Activation Potential and fire the cell. WIthout adequate Calcium there will be insufficient or no gradient and Calcium will not "flow" and thus will not create the necessary action potential to cause the cell to fire.

Sorry for the confusion,

When I said Ca++ binds to these channels, I was talking about the Sodium voltaged gated channels.

What you're talking about are two different things.

As Focker has mentioned, this mechanism is explained in Guyton and Hall. Also this concept is taught in depth by Dr. REINKE @ TWU, whose one of the most proven and well known A & P professor in the anesthesia community.

Volatile,

Ca++ does not bind to Potassium channels receptors, in this case of this discussion at least. in the focus of this discussion it is the opening of Ca++ channels that causes activation of the membrane by the ability of Calcium to flow through the opened channel thus causing depolarization of the membrane and subsequent activation of the cell. YOu are right that this is indeed dependent on/influenced by Potassium channel activation/Potassium gradient flow.

quanitative presense (or absence) has nothing to do with a membrane receptors ability to make "it is easier to cause a conformational change to open these channels". activation of the channel, ie-your "conformational change" is based solely on the presense of an agonist or strong voltage change to initiate the receptors operation. the quanitative involvement has to do with the number of receptors that are activated and the amount of Ca++ present to flow down the channel to cause a voltage change in order to overcome the Activation Potential and fire the cell. WIthout adequate Calcium there will be insufficient or no gradient and Calcium will not "flow" and thus will not create the necessary action potential to cause the cell to fire.

I agree with volitile's previous post

in addition:

In synaptic transmission, an action potential occurs(involving sodium and potassium in smooth, skeletal and in nerve impulse transmission), that open voltage gated calcium channels, allowing the in-flow of calcium which directly causes neurotransmitter vesicles to undergo exocytosis.

Increased ECF calcium will bind to Sodium gates, making it harder for sodium to bind to the sodium voltage gated channel, and create a conformational change that opens the channel, therefore it takes longer for enough sodium influx to reach threshold potential. Increased ECF calcium also raises the threshold potential, again making it harder to create an action potential, but, when an action potential is reached, a greater number of neurotransmitter vesicles are released. This means on the post-ganglionic nerve, more Ach receptor ion channels will open, more sodium can influx and reach a new action potential on that cell more quickly.

"Increased ECF calcium also raises the threshold potential, again making it harder to create an action potential, but, when an action potential is reached, a greater number of neurotransmitter vesicles are released."

Partly true. ECF can and does raise Action Potential Threshold making it "more difficult" for an action potential to be stimulated. But when the action potential is reached it does NOT increase or decrease the amount of neurotransmitter released at the axon terminal or increase or mitigate the desired signal in the case of cardiac rhythmic cells. Action Potentials are all or nothing. They either fire or they don't. when fired they propogate the signal that particular cell is programmed to release/trasmit. no more. no less. it the accumulation of all the cells' signals together that increase or decrease a particular response.

"Increased ECF calcium will bind to Sodium gates, making it harder for sodium to bind to the sodium voltage gated channel, and create a conformational change that opens the channel, therefore it takes longer for enough sodium influx to reach threshold potential."

False. calcium does bind to a variety of substrates/receptors etc but it does not bind to sodium channels. Nor does sodium bind to voltage-gated sodium channels. If you check your semantics in that paragraph you can see where the discrepancy falls. they're voltage-gated sodium channels, not sodium voltage gated channels. ie- as a specific, sufficient voltage is passed onto the region wherein the voltage-gated sodium channels reside these channels open allowing sodium to travel down the channel, further propogating the signal. ie- VOLTAGE induces a conformational change that opens the channel to allow sodium to travel into the cell and ultimately depolarize the cell or the region of the axon, in the cases of a neuron, in which those channels resided.

"open voltage gated calcium channels, allowing the in-flow of calcium which directly causes neurotransmitter vesicles to undergo exocytosis."

True. once voltage-gated calcium channels are opened by the action potential propogation to the axon terminal, calcium rushes in and binds to proteins that induce release of neurotransmitter vesicles to targeted axons dendrites.