Why does depolarisation by high intracellular K+ trigger calcium channels opening?

Question

I have learnt that in pancreatic beta cells, glucose being metabolised in the cell causes a high ATP level, which triggers ATP-dependent potassium channels to close. This means that potassium can't leave the cell anymore, which depolarises the membrane and causes voltage-gated calcium channels to open and release calcium into the cell to trigger insulin release. I don't understand why this happens, because both potassium and calcium being positively charged. Wouldn't this depolarise the membrane even more? I thought this would be unfavourable.

Answer 1

Ca²⁺ is very often the trigger to release neurotransmitter or, in this case, hormones. Ca²⁺ entry in the cell is important to activate the fusion of secretory vesicles with the membrane in pancreatic beta cells as shown in Fig. 1 (Thurmond, 2000). The function of Ca²⁺ entry is not so much related to its depolarizing actions.

^{Fig. 1. Ca2+-mediated insulin secretion. Glucose-stimulates insulin secretion by increasing the ATP/ADP ratio, which inhibits the ATP-sensitive KATP-channels, leading to membrane depolarization and opening of voltage-dependent calcium channels (VDCC), with a resultant major increase in cytosolic calcium, which, in turn, triggers exocytosis. SNARE proteins play a critical role in insulin granule secretion. The linking of the plasma membrane proteins syntaxin and SNAP-25 to vesicle protein VAMP-2/synaptobrevin-2 cause the docking of the vesicle, bringing insulin granules in close contact with the plasma membrane and calcium channels, after opening of calcium channels, the readily releasable pool (RRP) insulin granules located nearby are exposed to high level of Ca2+, resulting in RRP granule exocytosis. Source: Ren et al. (2007)}

Ca²⁺ entry in the cell is potentially toxic and closely regulated. For example, internal stores are actively involved in the release and re-uptake of Ca²⁺ (Pian-Smith et al., 1988). Although Ca²⁺ influx will depolarize the cell further, it will not contribute substantially to the membrane potential compared to the effects of K⁺ and Na⁺.

<sub>References
- Pian-Smith et al., Endocrinology (1988); 123(4):1984-91
- Ren et al., J Transl Med (2007)
- Thurmond, Landes Bioscience (2000)</sub>

Answer 2

First of all, this is a complex question with no easy answer. Ion channels and electrophysiology can be a very confusing topic. Part of the challenge to understanding these processes is that you need to be able to remember that ions (e.g. sodium, potassium and calcium) are not only trying to move towards chemical equilibrium, but also electrical equilibrium as well.

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In the pancreatic beta-cell insulin secretion is tightly regulated. As you state in the question, glucose enters the beta-cell and is metabolized creating an INCREASE in the ATP content of the cell. This increased ATP binds to ATP-sensitive potassium channels and CLOSES them. Remember, these channels are typically OPEN and allow potassium to normally flow OUT of the cell (because that would be potassium flowing DOWN its concentration gradient... potassium concentration is higher inside the cell than outside the cell). Note: This is the opposite for calcium, which would flow INTO the cell and down its concentration gradient (calcium outside the cell is higher than calcium inside the cell).

At the same time the ATP-sensitive channels are acting, there are Na/K ATPase pumps at work to move sodium OUT of the cell and potassium INTO to the cell (against the concentration gradients of both those ions). When the ATP-sensitive potassium channels close, it causes a build up of potassium INSIDE the cell because you have made the cell less permeable to potassium (when potassium can't flow OUT of the cell through the CLOSED ATP-sensitive channels it makes the membrane less polarized - i.e. become less negative or more positive - however you want to think about it).

When the cell reaches a threshold potential (that is, when it becomes depolarized to a certain point), it will cause opening of a type of voltage sensitive calcium channels. At this point, calcium channels open and allow calcium to flow down its concentration gradient and INTO the beta-cells. This calcium entry is required for the release of insulin vesicles through a mechanism that is outside the scope of this question, but unrelated to the calcium channels opening and closing.

The interesting thing about the calcium channels is that they INACTIVATE after a short amount of time and CLOSE on their own. Inactivation and closure is an intrinsic property of that type of calcium channel, and the channels do not REACTIVATE until the cell returns to being polarized once again. This inactivation is what limits the amount of calcium flux INTO the cell, which as mentioned in the other answer can be toxic to the cell.

So, in brief... the ATP-sensitive potassium channels CLOSE, the cell depolarizes when it reaches the threshold potential for the voltage-sensitive calcium channels. Those calcium channels open, calcium flows into the cell and works with other machinery to cause insulin secretion. In the meantime, the calcium channels quickly inactivate and close. The basal ion pumps then return the membrane potential back to its resting state. This return to a polarized resting state allows the voltage-gated calcium channels to 'reset' or reactivate, and then the entire process can occur once again.

I have simplified the explanation and left out some extraneous details - for more information about the specific types of channels see the references.

References to Read More:

(1) Review discussing ATP-sensitive potassium channels and voltage gated calcium channels in insulin secretion.

(2) Comprehensive review from the Endocrine Journal on insulin secretion, which discusses specifically both fast and slow calcium channels, inactivation and insulin secretion.

(3) Review talking about voltage gated channels in insulin secretion from the journal Diabetes.

(4) Open access article with a heavily detailed figure of the beta cell. However, has the different types of calcium channels and other ion channels to help with the understanding of this complicated topic.