Calcium channels determine how life begins, and ends
Ongoing work at Weill Cornell Medical College in Qatar (WCMC-Q) is investigating how intracellular calcium (Ca2+) signaling pathways are involved in the very beginning of life as they prepare the egg for fertilization and the initiation of embryogenesis. The National Priorities Research Program-funded work also has wider implications. Since all cells use Ca2+ signals, these studies could impact the treatment of various pathological conditions including infertility, hypertension, and cancer.
Cells in the human body need to be able to sense their environment in order to respond to cues to perform some function. Intercellular signaling, using hormones sent from one part of the body to another, allow, for example, the brain to tell your hand to pick up a pen as neurons in the brain fire action potentials to trigger the relevant muscle actions. For other cells, the message may be to divide or to die if infected by a virus.
However, in addition to these intercellular signals (signaling between cells), intracellular signals (those within a cell) also play a very important role in almost all functions of life as we know it. The hormones hit the cell surface receptor and that gives a signal within the cell to tell specific enzymes to perform certain functions. One of the most important intracellular messengers is the Ca2+ ion. It is involved in cell division, cell secretion, cell cycle progression, cell death, muscle contraction and action potential firing.
A basic understanding of the cellular and molecular biology of how these signals work is important as all cells use them, hence the findings may be applied to physiology or pathology because the molecules which generate a calcium signal are the same - whether they are functioning in the context of a nerve cell, fibroblast or hepatocyte. Understanding them in one system allows that work to be translated to another system, which may be more difficult to study. Thus these models can be used to understand higher-level complexity.
The work at WCMC-Q focuses on the development of a single cell in the ovary to form a viable ovum and how that egg fuses with sperm to start the process of forming an embryo. Calcium plays a prominent role in this whole process. How does the egg know to go ahead and make an embryo? How does the egg know that a sperm has fused with it? This is all down to calcium signaling.
Interestingly, a fully-grown oocyte in the ovary of any mammal or vertebrate is not fertilizable. It doesn't know how to go on and make an embryo, even if sperm is injected into it. The oocyte seems to 'acquire' this information after ovulation as the egg is travelling down the fallopian tube. This is known as oocyte maturation and is essential to prepare the egg to sustain the earlier phases of development.
So, calcium signaling is involved in this maturation phase, but how exactly? Calcium signals can come from one of two sources, intracellular stores or outside of the cell. There are channels which regulate both. One channel which regulates intracellular calcium release is the IP3 receptor. It is a channel sitting on the endoplasmic reticular membrane which releases calcium. The other channel which sits on the plasma membrane is the store-operated calcium entry channel, or SOC. Both channels are modulated during oocyte maturation to allow the egg to activate at fertilization.
The calcium signal, which has very specific spatial and temporal properties, tells the cell what it has to do, and the order in which these events must happen. For example in an oocyte, this list includes:
- Block polysperm. Only one sperm can enter the cell otherwise there will be mix of DNA and the cell will die.
- Pronuclei, which contain DNA from oocyte (mother) and sperm (father) must fuse.
- Finish the cell cycle (meiosis)
- Extrude the polar body (discard half of the DNA)
One of the most important findings so far is that the store-operated calcium entry pathway is completely inhibited in meiosis. This is also the case during mitosis. Understanding the molecular mechanisms controlling this inhibition will provide important insights into the regulation of Ca2+ signaling during cellular division, with implications on cancer, which results following uncontrolled cellular proliferation.
SOC is also critical for the development of the immune system and skeletal muscles since animal models and human beings with defective SOC suffer immunodeficiency and skeletal muscle problems. Generally, these people do not live for long.
The most recent research from Dr. Khaled Machaca's laboratory at WCMC-Q has been focusing on how this pathway is inhibited during the cell cycle. The store-operated Ca2+ entry pathway is made of a channel at the cell membrane (Orai1) and an endoplasmic reticulum (ER) membrane protein, STIM1, that activates Orai1 when ER Ca2+ stores are depleted. Machaca's lab found that during meiosis, Orai1 is no longer at the membrane, but is taken inside the cell and that is how the pathway is inhibited. In addition, STIM1 function is also inhibited during cellular division contributing to SOC inactivation.
Furthermore, their work is also looking at the trafficking of Orai1, how it goes to the membrane and how it regulates the cell cycle. If that channel doesn't make it to the membrane, you don't get SOC, which is essential for physiological function.
The research, with the support of QNRF, promises to continue to find new ways that intracellular signalling may be able to treat genetic disease, infertility and cancer.
Calcium signaling mechanisms in oocyte development and pathology
LPI Name: Dr. Khaled Machaca
Cellular ion homeostasis: the role of TRP channel oligomerization
LPI Name: Dr. Khaled Machaca