Anavex Life Sciences Corp (AVXL)

[blu_1]

More here on 273's action on the sigma 1 receptor. I won't be commenting here on its action on muscarinic receptors. The below 4 paragraphs, in quotation marks, are excerpts I took from the linked article below. The article talks about mitochondrial uptake of calcium ions (Ca2+). Figure 2 of the article shows a calcium channel on the membrane of the endoplasmic reticulum (ER). The figure doesn't show it, but a sigma 1 receptor is often located right next to that channel. When 273 binds to that sigma 1 receptor, that causes stored Ca2+ in the ER to flow thru the channel. Once outside the ER, the Ca2+ is rapidly taken up by the nearby mitochondria. The influx of Ca2+ into the mitochondria stimulates it to make ATP (ATP provides energy to carry out all cellular functions). In a neuron (brain cell) with dysfunctional ER-mitochondria interactions, additional ATP is needed to be generated by the mitochondria to establish homeostasis (end of dysfunction) between the ER and mitochondria. Once homeostasis is achieved, the ER will get back to properly arranging and folding proteins, such as amyloid, Tau, and enzymes. Thus, it will no longer produce misfolded amyloid leading to plagues, no Tau tangles, nor enzymes that don't function properly.

As an aside, the article mentions that a strong influx of Ca2+ into the mitochondria for a prolonged length of time can actually cause cell death! 273's affinity and bond to the sigma 1 receptor must be just right to trigger the release of just the precise amount of Ca2+ from the ER into the mitochondria. The amount and rate of Ca2+ flowing into the mitochondria produces different signals for the cell to carry out. The flow of Ca2+ initiated by 273 signals the mitochondria to generate the required amount of ATP needed to restore homeostasis. I've read elsewhere that agonists of receptors can have too low an affinity or too high an affinity for receptors to be of much benefit, or their action may actually harm the cell. Imagine an agonist of very high affinity binding to the sigma 1 receptor. It's gonna have a strong, persistent affect on that receptor. If the receptor is a sigma 1 on the ER, A LOT of Ca2+ is gonna flow from the ER to the mitochondria for a long time. If that flow is too strong and for too long, that will not send the proper signal to the mitochondria to restore homeostasis. In fact, it might even signal the cell to self destruct (apoptosis). Not good. Donepezil has a very high affinity for sigma 1, probably too high to send the correct signal to the mitochondria.

"The ability of mitochondria to capture Ca2+ ions has important functional implications for cells, because mitochondria shape cellular Ca2+ signals by acting as a Ca2+ buffer and respond to Ca2+ elevations either by increasing the cell energy supply or by triggering the cell death program of apoptosis. A mitochondrial Ca2+ channel known as the uniporter drives the rapid and massive entry of Ca2+ ions into mitochondria.

The net result of the increase in [Ca2+]mit is to increase the respiratory rate, H+ extrusion and ATP production. The [Ca2+]mit dependency of mitochondrial bioenergetics enables mitochondria to decode Ca2+ signals, and thus to tune ATP synthesis to the energetic requirements of the cell [9], [10] and [11]. However, prolonged increases in [Ca2+]mit can induce the opening of the mitochondrial permeability transition pore (PTP) leading to mitochondrial swelling, cytochrome C release, and cell death by apoptosis [12] and [13].

...the central role played by two organelles in cellular Ca2+ homeostasis: the endoplasmic reticulum (ER) and mitochondria. The ER is the major intracellular Ca2+ stores of cells, whereas mitochondria shape and decode cellular Ca2+ signals by taking up and then releasing Ca2+ ions. The Ca2+ uptake mechanisms of mitochondria have attracted much attention recently, due to the central role of mitochondria in cell metabolism and cell death.

Functional and morphological evidence indicate that mitochondria are in close contacts with the endoplasmic reticulum (ER) and with cell membrane channels [33]. The close contacts between the ER and mitochondria have received much attention, and several proteins have been proposed to link mitochondria to the ER."

http://www.sciencedirect.com/science/article/pii/S0005272810005797