Category Archives: Cell physiology

Not seeing what is obvious

Sometimes we need an eye-opener to notice things which are in our reach and still beyond comprehesion. We smite our forehead and confess how could we be such blinds. The paper “The essence of female–male physiological dimorphism: Differential Ca2+-homeostasis enabled by the interplay between farnesol-like endogenous sesquiterpenoids and sex-steroids? The Calcigender paradigm” by Arnold de Loof in “General and Comparative Endocrinology” is such an eye-opener. It puts the Calcium (Ca) metabolism in an entire new prospective. De Loof argues that Ca is a toxin which has to be kept away and that reproductive activities such as egg laying and mild production have developed for this purpose since the Ca that an egg contains and which is in milk deplete the organism of much Ca.

The Ca concentration in blood is in the range of 1-3 mM in man and are conserved in evolution. In the cell however, there are only 100 nM, ten times less. The cell membrane is partially permeable for Ca so that the cell always has to deal with an excess of Ca which is permanently depleted by Ca export or/and storage in entoplasmatic reticulum vesicles.

The surprise of the paper is that de Loof finds a function for farnesol in eukaryotes: A Ca transporter in the ER that is only regulated by farnesol-like substances is common to vertebrates and insects.

Whether all the ideas of the paper will survive experimental scrutiny is to be seen, but two ideas stick: Calcium as a toxin and its role or more to the point the removal of Calcium at the origin of reproductional activity.

The paper is open access and and a must.

Sirtuin protein at the start of GnRH neuron migration

The GnRH neurons are unique among the hypothalamic neurons that they originate not in hypothalamus itself, but in the vomeronasal organ of the olfactory bulb and move (in the mouse) between day 10 and 17 of embryonic development into the hypothalamus via the forebrain. When this wandering is impaired, there is not any GnRH synthesis in the hypothalamus due to missing GnRH neurons, a phenomen called Kallmann syndrome, and subsequently the patient undergo hypogonadotrophic hypogonadism.

In a report in Molecular Endocrinology this week Gabriel Di Sante and colleagues from Philadelphia with the help of Canadian coworkers from Ottawa describe in mice another protein involved in this wandering of neurons. They found that the Sirt1 protein is necessary to start the migration of GnRH neurons. Sirt1 is the analogue of sirtuin protein originally found in yeast as Silent regulatory protein and has diverse physiological functions. Sirt1 defective mutants are not viable and die in utero.

The paper shows that the migration is initiated intracellularly due to the interaction of FGF8 and the FGF receptor, Sirt1, and corstatin, whereupon the sirtuin protein leaves the nucleus and deacylates the cytoplasmatically located corstatin. This interaction then makes the neuron migrate. There are other mechanisms listed in the introduction of the article which effect the migration. But none is as near to the origin of the migration as this one.

A nice piece of work! Recommended!

Seeing that they see differently

What we see is determined by the visual pigments of the human eye. We have often asked what our dog might see. Colour vision was thought restricted to the primates. Totally wrong. Thanks to a paper by Justin Marshall & Kentaro Arikawa in Current Biology we know now that colour vision is very common in the animal kingdom. There are several species that use a much broader spectrum to look at their surroundings. Honey bees for example can identify objects in the UV part of the spectrum. They have, however, three different photoreceptors like humans. Waterflees or the Blue Tit have four different ones the former sensing the whole spectrum from 300 nm to 700 nm. The latter misses some light in the infrared part. Horses and dogs have only two different photoreceptors, they are in way green–red blind. Dogs, however, have a much more discriminating capacity in the dark.

What comes as a surprise is that butterflies and other insects can differentiate the visual reception with up to 8 different photoreceptors. And this is not the end: Shrimps have 20: (cited from the paper)”Twenty receptor types have been defined: twelve for colour, six for polarisation and two with overlapping function for luminance tasks”.

An eye-opener. Nice and Recommende!

Gray matters in grass research

Whether long-term marijuana smoking has robust effects for the human brain has been a matter of debate. In a paper in PNAS Silbey and colleagus from Dallas, Frisco, and Albuquerque have addressed this question using “multimodal measures in a large group of chronic marijuana” smokers. They claim that marijuna smokers the longer the more have decreasing gray matter in orbitofrotal cortex (OFC).

This part of the brain (citation from wikipedia:)

is considered anatomically synonymous with the ventromedial prefrontal cortex.[2] Therefore the region is distinguished due to the distinct neural connections and the distinct functions it performs.[3] It is defined as the part of the prefrontal cortex that receives projections from the magnocellular, medial nucleus of the mediodorsal thalamus, and is thought to represent emotion and reward in decision making.[4] It gets its name from its position immediately above the orbits in which the eyes are located. Considerable individual variability has been found in the OFC of both humans and non-human primates.

The authors are very cautious to attribute these changes to THC. They also found increased connectivity within the OFC and suggest that the OFC gray matter is more vulnerable to the THC effects.



When timing matters

When you are an endocrinologist you know that hormones are released into the circulation in pulses and that melatonin is only produced in the dark, that glucocortoids concentrations in the blood are high during the night and low during the day, that many hormones have their rhythm. Every hormone has its time, as the prophet sayed.

However, what has not been known until now is that to the same extend more than 40 % of all genes are expressed in a circadian (day long) rhythm.  Zhang and colleagues measured in the mouse ( and the might be the only shortcoming of the study ) the gene expression with arrays to determine many gene simultaneously in every hour of the day and night. They found 43 % of all genes expressed in a circadian rhythm. They also determined noncoding RNAs  and found 1000 of them cycling.

There are consequences for medicine and therapy: The targets of the top most drugs are expressed all in (specific) rhythms: When a drug like aspirin for example is taken at the wrong time, it would be gone before the target is fully expressed. The scale of this problem seems tremendous. Any pharmaceutical company has to do its home work again. But on the other hand, therapy might become more reliable which would be a large improvement.

The circadian rhythm in the 12 organs analysed are quite different. It might take some time to get used to the thinking that genes in question are not stable during the day but change the level of expression. It will be interesting to follow the aftermath of that paper. The paper is open access and therefore free to everybody.

A must.


Who is my neighbor?

To form stable connections to your neighbors is  a way to make daily life predictable even if the relations are inimical. Looking at an amino acid in a three-dimensional structure is likewise to look for neighbors at the amino acid level. This problem of protein folding has occupied biochemists for quite some time. Even with the biggest supercomputers it could not sufficiently be simulated.

In a Perspective article in PNAS Englander and Mayne from the Univ. Pennsylvania present the problem and the new technology which has helped to solve at least one structure’s folding. They show what is possible now and what cannot be done. At the origin of the problem are small units of folding which the form or donot form extended structures. Deuterium/hydrogen exchange experiments and their fast time-line-records are what can give information about the ways protein fold. This is an actual picture what has been achieved in the field. It is more that one could expect from the outside, but not enough to solve the puzzle. It seems at least that a mechanism of protein folding has been found.

Worth reading!

How an ABC transporter gets rid of arsenic

Not only from Agatha Christie’s books we know that arsenic is toxic. It is even a carcinogen and, most importantly, is contaminating the groundwater in a lot of countries. Removing arsenic from water and food is a tremendous task and will improve the health of many people.

Therefore a paper on an ABC transporter in rice which excludes arsenic from the grains is a welcome addition to the tasks involved. ABC transporter are evolutionary very old molecules which transports ligands across membranes with the help of ATP. Song and colleagues found out that the rice (Oryza sativa) the ABC transporter C1 (OrABCC1) lowers the arsenic content in the grain therefore the food is not contaminated in the way the water it is grown is. The molecule is also expressed in other parts of rice. When genetically engineered into wheat, it could transfer the resistance to arsenic. In rice, its expression is increased when arsenic gets higher. It is arsenic specific, since when knock-out the arsenic resistance was gone but not the cadmium resistance.

Immunologists will know ABC transporters involved in the transfer of degraded peptides into the ER to be loaded eventually into the histocompatibility class I molecules. Obviously, they can do much more.


“Sport ist Mord”

Obviously there is no easy translation for this German proverb: No sports, no sports is what Churchill said. Sport’s a killer, sport is murder doesn’t have the rhyme the German version has. Nevertheless, the people who say so are totally wrong. Exercise was the base that the human race could go where we are now, a overweight race with many problems due to sitting most of the time in our desk chairs while exercise is beyond the horizon and reserved to leisure. It had been just the opposite: running and hunting was the professional occupation and sitting at the fire the leisure. How time changes!

I was lead to this excurs by a review in Cell: Integrative Biology of Exercise by Howard and colleagues from Melbourne (Australia), Rochester (Maine), and Stockholm (Sweden). They bring the different aspects of Exercise into an systematic overview and nail the “Major Signaling Pathways Involved in the Control of Skeletal Muscle Hypertrophy and Mitochondrial Biogenesis” down to one image. Exercise involves “Complex and Redundant Physiological Control” in CNS, muscles, heart, lung, in the metabolism and neuroendocrine systems. The pictures are straight forward and very instructive. 


Once a month …

The selective activation of only a few of several hundred thousands primordial follicles to mature into an oocyte is a riddle which has not at all been solved. In a paper in Current Biology Chang and colleagues from Gothenburg, Sweden, place this decision onto the microenvironment of the primary cell, especially the few primordial follicular granulosa cells surrounding each primordial follicle. They show that mTORC1 activation and Kit ligand signalling are required steps in the activation, mTORC1 defective animals never develop primary follicles, the primordial follicular cells die.

They do not answer the question which follicle is to grow, but placing the decision to the surrounding is a paradigma change and will focus the experiments and the discussion away from the oocyte precursors which cells seems more or less “only” to react to the surroundings. Given that this cell is dormant and needs strong signals to be activated this is comprehensible. At least we know now who the cascade of events is initiated.

Whether this has consequences for in vitro fertilization we will see. The question why so few follicles are activated during the reproductive life of women is not answered by this article.

Nice and recommended!

Mother’s age a newborn’s risk factor — due to mitochondrial DNA

Mitochondrial DNA (mtDNA) is used to assign traits in human evolution: for example it was claimed that the Ur-mother of modern humans lived in Africa. mtDNA may harbor fatal mutations which cannot be treated. If there occurs a mutation during the life of an individual this mutation is rarely fatal since it is well diluted. However, if a women during oogenesis transfers these mutation to the oocyte, the problem is multiplied since there are only some mtDNA molecules transferred and therefore one mutation might result in diseases like diabetes, cancer, male infertility, Parkinson, or Alzheimer. The male mtDNA does not reach the progeny.

In an article in PNAS Rebolledo-Jaramillo and colleagues have analyzed in detail mutation rates, disease accumulation and dependency of the age of the mother on the frequency of mutations in the child. They show that on average 9 mtDNA molecules are transferred to the oocyte. The mutation rate is 1.3 × 108 /year (10 times higher than for genomic DNA) which means a mutation in about every 78 th mitochondium (mitochondium has 16.5 kB).  They found also, and that is easily comprehensible, that the older the mother the higher the risk of a defect mitochondrium for the child. Ten years older means a tenfold higher risk.

This risk is independent of fathers since only the maternal mtDNA is inherited. There might be other risks due to age in man but they have to be analysed.

Nice and careful article! Recommended!