Week 2- The Rough ER and Calcium’s Role in Heart Attacks

Anita M -

Much like the previous week, I have been studying human physiology and learning lots of cool fun stuff. For example, did you know that there is a high calcium concentration in the rough ER and a low calcium concentration in the cytosol. When Calcium ions move down that concentration gradient from the Rough ER and into the cytosol, it signals for muscle contraction. When the movement of calcium ions is disrupted in heart cells, it can contribute to problems with heart contraction and relaxation. Attached is a diagram explaining this concept with pictures.

For those who have experienced a lack of blood supply to the heart following a heart attack, or myocardial infarction reperfusion (MI/R), an overload of calcium occurs within heart cells. This disrupts up the calcium gradient, can lead to further inflammation of heart tissue and exacerbate the other adverse effects of MI/R, such as heart failure.

Currently, researchers are working on formulating medications and therapies that can more effectively inhibit calcium overload. Understanding the different roles the ER plays in relation to heart disease is vital to better understand how modifications to the ER (one of which, is ATF6 activation,) can help cure heart disease.

Next week, I will most likely still be sharing more fun facts with you guys until I can finally start my own experiments in the lab.

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Comments:

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    mihika_g
    This is a great topic Anita! When you start your own work in the lab, what do you hope to focus on initially, or what would your first steps look like?
    February 19, 2025 at 2:42 pm - Reply
    Arnab
    So cool, but could you please explain this question I have: Given that ATF6 activation plays a role in modifying the ER's function in heart disease, how might the unfolded protein response and ATF6-mediated transcriptional regulation influence calcium homeostasis in myocardial infarction/reperfusion (MI/R) injury? Given your knowledge on the subject, what specific mechanisms of therapeutic targets could be employed to overcome this unwanted influx of Ca 2+ ions. Thank you
    February 19, 2025 at 9:07 pm - Reply
    Akash Joseph
    Hi Anita, This is so exciting! Are there any markers that would allow early detection of disruption to these calcium gradients? Thrilled to tune back in next week :)
    February 20, 2025 at 3:51 pm - Reply
    anita_m
    Hello Mihika, Great question! My first steps would be culturing cells. Within those cells, I will activate ATF6 and then measure protein expression of GRASP55.
    February 20, 2025 at 4:10 pm - Reply
    shreyash_p
    Hello Anita, great work all around. I'm curious: how might future therapies or drugs target this calcium overload in the rough ER to help prevent further damage after a heart attack? Thank you!
    February 20, 2025 at 4:34 pm - Reply
    Anita
    Hey Arnab, ATF6 activates the unfolded protein response (UPR) and plays a role in maintaining proteostasis within the cell by helping to destroy any misfolded proteins. The UPR acts within the Rough ER, which is a major organelle of interest for my research project. So since ATF6 and the UPR deal with proteins they are not really involved in maintaining calcium homeostasis. However, a misbalance of calcium can lead to ER stress which can lead to the build up of misfolded proteins. This causes the UPR and thereby ATF6 to be activated. It is also important to keep in mind that chronic ER stress leads to heart failure, which is why the overload of calcium for patients with MI/R injury is so detrimental. Many protein channels help to regulate calcium homeostasis, such as LTCC and NCX. So targeting those through calcium-channel blockers (CCBs) like nifedipine, nisoldipine, diltiazem, etc. originally appeared to a be promising way to prevent the unwanted influx of calcium. However, CCBs are not 100% effective, so researchers started developing drugs like adenosine, vorapaxar, and metoprolol which target calcium signaling pathways instead.
    February 21, 2025 at 9:03 pm - Reply
    anita_m
    Hi Mr. Joseph, Thank you for your question! Many protein channels control calcium influx, such as LTCC, NCX, SERCA, RyR2, PLB, and FKBP12.6. Monitoring these protein channels can help in early detection of calcium dyshomeostasis. Likewise, proper inhibition of these proteins can help in prevention of calcium overload. There also also blood tests that can inform us of intracellular calcium levels.
    February 28, 2025 at 11:06 am - Reply
    anita_m
    Hi Shreyash, Wonderful question! Current drugs target protein channels that help regulate calcium homeostasis, like LTCC, NCX, and PLB. Calcium-channel blockers (CCBs) such as nifedipine, nisoldipine, or diltiazem inhibit the functions of these protein channels, preventing unwanted calcium influx. CCBs help decrease symptoms for patients with MI/R, but are not fully effective which is why researchers began to develop new drugs (adenosine, vorapaxar, metoprolol, ridogrel, flunarizine, zoniporide hydrochloride) that target calcium signaling pathways. This method of treatment plays more of a preventive role for patients with MI/R than CCBs, helping to prevent further MI/R damage after a heart attack.
    February 28, 2025 at 11:23 am - Reply

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