Information

Are resonances the reason receptors work?


From Visual phototransduction - Wikipedia:

When struck by a photon, 11-cis retinal undergoes photoisomerization to all-trans retinal which changes the conformation of the opsin GPCR leading to signal transduction cascades which causes closure of cyclic GMP-gated cation channel, and hyperpolarization of the photoreceptor cell.

From the physics point of view, does this mean the proteins in the eye are combinations of oscillators, each of them in charge for a specific wavelength, so that if one oscillator resonates with the photon, the signal is produced? In general, does all receptors work this way? Note that physical oscillators should have exponential or sinusoid functions. See this Photography question: How to capture a swinging pendulum?


Photoreceptors themselves dont act as oscilators, a single receptor is either 'on' or 'off' - it does not respond differently to different wavelenghts. Humans have Trichromatic vision, which means that we have 3 different kinds of photo-receptors that respond differently to light of a given wavelength at a given intensity. By combining multiple signals from these 3 different receptor types the brain can translate this to different colors (its actually kind of similar to how RGB color works).

Therefore I would say that even photo-receptors don't work like oscilators, only their specific ligands switch between the 11-cis & trans state, but this is more of a statistical and physico-chemical process (which does involve resonance between the energy of the photons and the electrons in the cis bond)


Receptors accept a huge variety of molecules as ligands.
In the example that you outline the receptors are called photoreceptors. The ligands for photoreceptors are generally contain alkene backbones which switch cis and trans forms on exposure to a certain wavelength. The oscillator analogy holds true to a certain extent.
However, not all receptors function similar to photoreceptors. Photoreceptors are designed in a way to sense a wide signal spectrum (the visual spectrum). On the other hand receptors which work on a much local scale e.g. delta receptor for the notch ligand are not similar to oscillators at all i.e. there is no factor of resonance with external stimuli.


LDL receptor

The low-density lipoprotein (LDL) receptor (LDL-R) is a mosaic protein of 839 amino acids (after removal of 21-amino acid signal peptide) [5] that mediates the endocytosis of cholesterol-rich LDL. It is a cell-surface receptor that recognizes the apoprotein B100, which is embedded in the outer phospholipid layer of LDL particles. The receptor also recognizes the apoE protein found in chylomicron remnants and VLDL remnants (IDL). In humans, the LDL receptor protein is encoded by the LDLR gene on chromosome 19. [6] [7] [8] It belongs to the low density lipoprotein receptor gene family. [9] It is most significantly expressed in bronchial epithelial cells and adrenal gland and cortex tissue. [10]

Michael S. Brown and Joseph L. Goldstein were awarded the 1985 Nobel Prize in Physiology or Medicine for their identification of LDL-R [11] and its relation to cholesterol metabolism and familial hypercholesterolemia. [12] The LDLR gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. [13]


A Scientific Explanation of How Marijuana Causes the Munchies

It's one of the most well-known effects of marijuana: the powerful surge in appetite many users feel after smoking or ingesting the drug, colloquially known as "the munchies."

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For medicinal users that have trouble eating due to chemotherapy, this can be one of the drug's biggest benefits. For recreational users, this benefit can also be rather enjoyable, if unkind on the waistline. But for years, scientists have struggled to understand how marijuana's active ingredient—tetrahydrocannabinol, or THC—stimulates appetite.

A new study published today in Nature Neuroscience brings us a bit closer to solving the mystery. A team of European neuroscientists led by Giovanni Marsicano of the University of Bordeaux has found that, in mice, THC fits into receptors in the brain's olfactory bulb, significantly increasing the animals' ability to smell food and leading them to eat more of it. A big part of the reason why you might eat more food after using marijuana, the research indicates, is simply that you can smell and taste it more acutely.

This effect of THC has to do with the underlying reason why the chemical affects the human brain so potently in the first place. Likely produced by the marijuana plant as a self-defense against herbivores who might feel disorientated after eating the plant and avoid it in the future, THC fits into receptors that are part of the brain's natural endocannabinoid system, which helps to control emotions, memory, pain sensitivity and appetite. Our brains typically produce their own chemicals (called cannabinoids) that fit into these same receptors, so by mimicking their activity, THC can artificially alter the same factors in dramatic ways.

The scientists began by exposing mice (increasingly used in neuroscientific research because of the surprising amount of cognitive similarities they share with humans) to banana and almond oils as a test of sensitivity to scent. When they did so, the mice sniffed the oils extensively at first, then stopped showing interest in them, a well-known phenomenon called olfactory habituation. Mice that were dosed with THC, however, kept on sniffing, demonstrating an enhanced sensitivity to the scents. These THC-dosed mice also ate much more chow when given the chance, showing an increased appetite.

The researchers also genetically engineered some mice to lack a type of cannabinoid receptor in their olfactory bulbs and subjected them to the same experiment. They found that even if these mice were given THC, it had no effect: They still habituated to the scent, showing that the drug's scent-enhancing powers involved activity in this region of the brain. In addition, these mice did not demonstrate an increased appetite when given the drug, showing that the "munchies" effect was dependent on olfactory lobe activity as well.

The upshot of all this: If mice are an accurate model for humans, one of the ways that THC increases appetite is by making us more sensitive to the smells of food. Because scent and taste are so closely related, it likely allows us to better taste flavors as well. 

This new finding is likely just a piece of the THC-and-appetite puzzle. Previous research has found that the drug also acts on receptors in a region of the brain called the nucleus accumbens, increasing the release of the neurotransmitter dopamine—and the sensation of pleasure—that comes as a result of eating while high. Other work has found that THC additionally interacts with the same sorts of receptors in the hypothalamus, leading to release of the hormone ghrelin, which stimulates hunger.

The one aspect that ties together these disparate mechanisms is that they all involve the brain's natural endocannabinoid systems. THC—and, by consequence, marijuana—does much of its work by manipulating the same pathways that the brain uses to normally regulate the senses.

But perhaps most interesting is that the new study hints at a compelling metaphor for the way THC manipulates this natural system: it mimics sensations felt when we're deprived of food. As a final test, the researchers forced some mice to fast for 24 hours, and found that this drove up levels of natural cannabinoids in the olfactory lobe. Not surprisingly, these starved mice showed greater scent sensitivity and ate much more too.

Most intriguing, the genetically engineered mice with olfactory lobes that lacked cannabinoid receptors did not show increased scent sensitivity or appetite even when they were starved. This indicates that both THC and the natural cannabinoids that result from starvation are acting on the same neural pathway to allow us to smell and taste with greater sensitivity, and thus eat more. In other words, THC appears to give us the munchies by convincing our brains that we're starving.

About Joseph Stromberg

Joseph Stromberg was previously a digital reporter for Smithsonian.


Contents

Two alpha subunits and two beta subunits make up the IGF-1 receptor. Both the α and β subunits are synthesized from a single mRNA precursor. The precursor is then glycosylated, proteolytically cleaved, and crosslinked by cysteine bonds to form a functional transmembrane αβ chain. [5] The α chains are located extracellularly, while the β subunit spans the membrane and is responsible for intracellular signal transduction upon ligand stimulation. The mature IGF-1R has a molecular weight of approximately 320 kDa. citation? The receptor is a member of a family which consists of the insulin receptor and the IGF-2R (and their respective ligands IGF-1 and IGF-2), along with several IGF-binding proteins.

IGF-1R and the insulin receptor both have a binding site for ATP, which is used to provide the phosphates for autophosphorylation. There is a 60% homology between IGF-1R and the insulin receptor. The structures of the autophosphorylation complexes of tyrosine residues 1165 and 1166 have been identified within crystals of the IGF1R kinase domain. [6]

In response to ligand binding, the α chains induce the tyrosine autophosphorylation of the β chains. This event triggers a cascade of intracellular signaling that, while cell type-specific, often promotes cell survival and cell proliferation. [7] [8]

Tyrosine kinase receptors, including the IGF-1 receptor, mediate their activity by causing the addition of a phosphate groups to particular tyrosines on certain proteins within a cell. This addition of phosphate induces what are called "cell signaling" cascades - and the usual result of activation of the IGF-1 receptor is survival and proliferation in mitosis-competent cells, and growth (hypertrophy) in tissues such as skeletal muscle and cardiac muscle.

During embryonic development, the IGF-1R pathway is involved with the developing limb buds.

The IGFR signalling pathway is of critical importance during normal development of mammary gland tissue during pregnancy and lactation. During pregnancy, there is intense proliferation of epithelial cells which form the duct and gland tissue. Following weaning, the cells undergo apoptosis and all the tissue is destroyed. Several growth factors and hormones are involved in this overall process, and IGF-1R is believed to have roles in the differentiation of the cells and a key role in inhibiting apoptosis until weaning is complete.

Insulin signaling Edit

IGF-1 binds to at least two cell surface receptors: the IGF1 Receptor (IGFR), and the insulin receptor. The IGF-1 receptor seems to be the "physiologic" receptor - it binds IGF-1 at significantly higher affinity than it binds insulin. [9] Like the insulin receptor, the IGF-1 receptor is a receptor tyrosine kinase - meaning it signals by causing the addition of a phosphate molecule on particular tyrosines. IGF-1 activates the insulin receptor at approximately 0.1x the potency of insulin. Part of this signaling may be via IGF1R/insulin receptor heterodimers (the reason for the confusion is that binding studies show that IGF1 binds the insulin receptor 100-fold less well than insulin, yet that does not correlate with the actual potency of IGF1 in vivo at inducing phosphorylation of the insulin receptor, and hypoglycemia).

Aging Edit

Studies in female mice have shown that both supraoptic nucleus (SON) and paraventricular nucleus (PVN) lose approximately one-third of IGF-1R immunoreactive cells with normal aging. Also, old calorically restricted (CR) mice lost higher numbers of IGF-1R non-immunoreactive cells while maintaining similar counts of IGF-1R immunoreactive cells in comparison to old-Al mice. Consequently, old-CR mice show a higher percentage of IGF-1R immunoreactive cells, reflecting increased hypothalamic sensitivity to IGF-1 in comparison to normally aging mice. [10] [11]

Craniosynostosis Edit

Mutations in IGF1R have been associated with craniosynostosis. [12]

Body size Edit

IGF-1R has been shown to have a significant effect on body size in small dog breeds. [13] A "nonsynonymous SNP at chr3:44,706,389 that changes a highly conserved arginine at amino acid 204 to histidine" is associated with particularly tiny body size. "This mutation is predicted to prevent formation of several hydrogen bonds within the cysteine-rich domain of the receptor’s ligand-binding extracellular subunit. Nine of 13 tiny dog breeds carry the mutation and many dogs are homozygous for it." Smaller individuals within several small and medium-sized breeds were shown to carry this mutation as well.

Mice carrying only one functional copy of IGF-1R are normal, but exhibit a

15% decrease in body mass. IGF-1R has also been shown to regulate body size in dogs. A mutated version of this gene is found in a number of small dog breeds. [13]

Gene inactivation/deletion Edit

Deletion of the IGF-1 receptor gene in mice results in lethality during early embryonic development, and for this reason, IGF-1 insensitivity, unlike the case of growth hormone (GH) insensitivity (Laron syndrome), is not observed in the human population. [14]

Cancer Edit

The IGF-1R is implicated in several cancers, [15] [16] including breast, prostate, and lung cancers. In some instances its anti-apoptotic properties allow cancerous cells to resist the cytotoxic properties of chemotherapeutic drugs or radiotherapy. In breast cancer, where EGFR inhibitors such as erlotinib are being used to inhibit the EGFR signaling pathway, IGF-1R confers resistance by forming one half of a heterodimer (see the description of EGFR signal transduction in the erlotinib page), allowing EGFR signaling to resume in the presence of a suitable inhibitor. This process is referred to as crosstalk between EGFR and IGF-1R. It is further implicated in breast cancer by increasing the metastatic potential of the original tumour by conferring the ability to promote vascularisation.

Increased levels of the IGF-IR are expressed in the majority of primary and metastatic prostate cancer patient tumors. [17] Evidence suggests that IGF-IR signaling is required for survival and growth when prostate cancer cells progress to androgen independence. [18] In addition, when immortalized prostate cancer cells mimicking advanced disease are treated with the IGF-1R ligand, IGF-1, the cells become more motile. [19] Members of the IGF receptor family and their ligands also seem to be involved in the carcinogenesis of mammary tumors of dogs. [20] [21] IGF1R is amplified in several cancer types based on analysis of TCGA data, and gene amplification could be one mechanism for overexpression of IGF1R in cancer. [22]

Due to the similarity of the structures of IGF-1R and the insulin receptor (IR), especially in the regions of the ATP binding site and tyrosine kinase regions, synthesising selective inhibitors of IGF-1R is difficult. Prominent in current research are three main classes of inhibitor:

    such as AG538 [23] and AG1024. These are in early pre-clinical testing. They are not thought to be ATP-competitive, although they are when used in EGFR as described in QSAR studies. These show some selectivity towards IGF-1R over IR.
  1. Pyrrolo(2,3-d)-pyrimidine derivatives such as NVP-AEW541, invented by Novartis, which show far greater (100 fold) selectivity towards IGF-1R over IR. [24] are probably the most specific and promising therapeutic compounds. Those currently undergoing trials include figitumumab.

Insulin-like growth factor 1 receptor has been shown to interact with:

There is evidence to suggest that IGF1R is negatively regulated by the microRNA miR-7. [41]


Can Beta-2-Adrenergic Pathway Be a New Target to Combat SARS-CoV-2 Hyperinflammatory Syndrome?-Lessons Learned From Cancer

SARS-CoV-2 infection is a new threat to global public health in the 21 st century (2020), which has now rapidly spread around the globe causing severe pneumonia often linked to Acute Respiratory Distress Syndrome (ARDS) and hyperinflammatory syndrome. SARS-CoV-2 is highly contagious through saliva droplets. The structural analysis suggests that the virus enters human cells through the ligation of the spike protein to angiotensin-converting enzyme 2 (ACE2). The progression of Covid-19 has been divided into three main stages: stage I-viral response, stage II-pulmonary phase, and stage III-hyperinflammation phase. Once the patients enter stage III, it will likely need ventilation and it becomes difficult to manage. Thus, it will be of paramount importance to find therapies to prevent or slow down the progression of the disease toward stage III. The key event leading to hyperinflammation seems to be the activation of Th-17 immunity response and Cytokine storm. B2-adrenergic receptors (B2ARs) are expressed on airways and on all the immune cells such as macrophages, dendritic cells, B and T lymphocytes. Blocking (B2AR) has been proven, also in clinical settings, to reduce Th-17 response and negatively modulate inflammatory cytokines including IL-6 while increasing IFNγ. Non-selective beta-blockers are currently used to treat several diseases and have been proven to reduce stress-induced inflammation and reduce anxiety. For these reasons, we speculate that targeting B2AR in the early phase of Covid-19 might be beneficial to prevent hyperinflammation.

Keywords: Beta adrenergic receptors COVID-19 Cytokine storm SARS-CoV2 beta-blockers hyperinflammation immune response.

Copyright © 2020 Barbieri, Robinson, Palma, Maurea, Desiderio and Botti.

Figures

Proinflammatory cytokines in mice untreated…

Proinflammatory cytokines in mice untreated (Control) or treated with beta-2-inhibitor (ICI115,881). 12 Cytokine…

Summary of possible benefits of…

Summary of possible benefits of β 2-AR targeting in patients with Sars-Cov-2. Explanation…


4 theories on why so many coronavirus cases are asymptomatic

Since the start of the coronavirus pandemic, scientists have been puzzled about why many people who contract the virus develop symptoms of Covid-19 while others don't experience any symptoms at all. Now, recent research has produced a handful of theories, Ariana Eunjung Cha reports for the Washington Post.

Large numbers of asymptomatic patients

Data has shown that a large percentage of people who've been infected with the novel coronavirus do not experience symptoms of Covid-19, the disease the virus can cause. For instance, 88% of 147 infected residents at a Boston homeless shelter were asymptomatic, while 95% of the 481 people infected at a Tyson Foods factory showed no symptoms, Cha reports.

This trend is significant, Cha reports, because understanding what shielded asymptomatic individuals from severe illness could help researchers develop vaccines and therapies to treat Covid-19, or to potentially create ways to develop herd immunity against the virus.

Now, initial research is finally revealing some clues, Cha writes. Here are four theories research suggests may be the reason so many people infected with the new coronavirus are asymptomatic:

1. T-cell memory

One theory suggests that some people have partial immunity to the coronavirus due to so-called "memory" T cells&mdashwhite blood cells that run the immune system and are in charge of recognizing invaders, Cha reports.

For instance, researchers in a study published in the journal Cell compared blood samples from people recovering from Covid-19 with samples from uninfected people who donated blood between 2015 and 2018. According to the researchers, the T cells in 40% to 60% of the old samples appeared to recognize the new coronavirus&mdasha finding echoed by research teams in the Netherlands, Germany, and Singapore.

A related paper published this week in the journal Science suggested that this partial immunity could come from exposure to other coronaviruses, such as those that cause the common cold. And the immune system's strongest response, according to the study, was against the spike proteins used by the novel coronavirus to break into cells&mdashindicating "that fewer of these viral copies get past these defenses," Cha writes.

"The [new coronavirus] didn't even exist back [when the old blood samples were taken], so to have this immune response was remarkable," Alessandro Sette, one of the authors of the Science and Cell studies from the La Jolla Institute for Immunology, said. And citing the immune response to spike proteins in particular, Sette added, "The current model assumes you are either protected or you are not&mdashthat it's a yes or no thing. But if some people have some level of preexisting immunity, that may suggest it's not a switch but more continuous."

NIH Director Francis Collins said this theory could "potentially explain why some people seem to fend off the virus and may be less susceptible to becoming severely ill."

However, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, cautioned that the theory is premature, though he agreed that some partial, already present immunity in some patients is a possibility. "There are so many other unknown factors that maybe determine why someone gets an asymptomatic infection," such as age and overall health, he said. "It's a very difficult problem to pinpoint one thing."

2. Immunity from childhood vaccinations

Another theory suggests that childhood vaccines may have provided partial immunity against the new coronavirus for some patients, Cha reports.

Andrew Badley, a researcher at the Mayo Clinic, and his team collaborated with data experts from nference to examine 137,037 Mayo patient records to look for a link between vaccinations and infection from the novel coronavirus.

They found that seven types of childhood vaccines&mdashadministered one, two, or five years previously&mdashwere associated with having a lower infection rate from the coronavirus. This was especially true among people who recently received a pneumonia vaccine, which was associated with a 28% reduction in coronavirus-infection risk, and polio vaccines, which were associated with a 43% reduction in coronavirus-infection risk. And those associations held even after adjusting for a variety of factors, including geographic incidence of the virus, demographics, and underlying conditions, the researchers said.

However, since the study is observational and cannot show causality, researchers at Mayo are now looking at ways to quantify how the vaccines affect the new coronavirus, Cha reports. After all, as Badley pointed out, if existing vaccines end up being as effective against the coronavirus as vaccines currently under development, the finding could upend how countries are approaching vaccines against the novel virus altogether.

3. Biology

Researchers at NIH are looking into a theory that suggests ACE2 receptors may affect the severity of illness a person develops from the new coronavirus.

According to Cha, the coronavirus can "latch" onto ACE2 receptors, which in healthy people keep blood pressure stable, then travel through the body and replicate. Researchers are intrigued by the receptors because they've theorized that minimizing those receptors may obstruct the virus' ability to replicate or "trick the virus into attaching itself to a drug" instead, so it's not able to replicate and travel through the body, Cha reports.

In addition, counterintuitive findings suggest that "allergic reactions may protect you by down-regulating the receptor," Alkis Togias, an NIH researcher, said&mdashalthough he cautioned it was "only a theory."

Specifically, recent research has found that ACE2 receptors were diminished in children with lots of allergies and asthma&mdashfindings that, when paired with hospital data, indicate that asthma doesn't appear to be a risk factor for the new coronavirus.

As a result, Togias and his team are working on a study of 2,000 American families to see how ACE2 receptors are expressed differently as people age, hoping to better understand how the receptors affect the new coronavirus by comparing the receptors' differences and immune responses within the families, Cha reports.

4. Masks

Researchers are also exploring whether widespread mask use affects the severity of Covid-19, Cha reports.

Monica Gandhi, a researcher at the University of California, noticed how different asymptomatic case numbers were on two different cruise ships. On the Diamond Princess, where masks weren't used, 47% of those infected with the virus were asymptomatic. But on an Argentine cruise ship, where all passengers were given surgical masks and crew received N95s, 81% of cases were asymptomatic. Similarly, according to Gandhi, countries that implemented population-level mask mandates&mdashincluding the Czech Republic, Singapore, and Vietnam&mdash"got cases, but fewer deaths."

And Gandhi also noted, in an article published in the Journal of General Internal Medicine, that in some early coronavirus outbreaks where people weren't wearing masks, 15% of those infected were asymptomatic. However, later in the pandemic, when more people were wearing masks, asymptomatic rates jumped between 40% and 45%. Gandhi said that data indicates that masks may not only protect others&mdashas health officials in the United States have stated&mdashbut they may also protect the wearer (Cha, Washington Post, 8/8).


There May Be a Biological Reason the Wachowski Siblings Are Both Transgendered

The science behind the biological underpinnings of transgender is complicated and contested.

Director, screenwriter, and producer Lilly Wachowski (formerly Andy) announced Tuesday that she is a transgender woman. Wachowski’s statement comes about four years after her sister, Lana, announced she was living publicly as a transgender woman. The Wachowski siblings are famous for work including The Matrix trilogy, V for Vendetta, and the Netflix series Sense8.

Wachowski released her statement in the Windy City Times after being threatened by The Daily Mail that the “definitely not a tabloid” organization was going to profile her transition against her will. She wrote:

Because Wachowski shares the same gender identity as her sister, public curiosity begs the question: Is it possible that there is some biological reason that siblings would both have a transgender identity?

The answer is, to put it mildly, complex.

“There are likely several pathways towards a transgender identity and there are indicators that there may be a biological basis for transgender identity, but it isn’t yet very clear,” biologist and neuroscientist Rachel Levin told Inverse. “I strongly suspect that there are biological underpinnings to many of the major roots to being trans — but that’s not to say there is only one root. The science needs to be cleaned up.”

Levin is the Chair of Neuroscience at Pomona College and a contributor to the academic volume Trans Bodies, Trans Selves. While she has doubts about any science being conclusive, she says some studies do suggest a possible role for biology and genetics in determining gender identity.

The most famous biological evidence comes from research conducted by psychologist Antonio Guillamon and neuropsychologist Carme Junque Plaja. In 2013, the pair used an MRI to examine the brains of 24 females who made the transition to males and 18 males who transitioned to females, before and after they went through hormonal treatments. They found that before these individuals went through treatment, their brains resembled the brains of their experienced gender. The cortical regions in the right hemisphere of the brains of male-to-female subjects tender to be thinner, which is a characteristic of the female brain. On the other side, the females who transitioned to males had relatively thin subcortical areas in their brain, which is typical of male brains.

Milton Diamond, director of the Pacific Center for Sex and Society at the University of Hawaii, tells Inverse that “there is definitely a genetic connection.” In a 2013 study, Diamond found that there is a statistically higher instance among twins that if one twin is a transgender individual, then the chance that the other twin will be a transgender individual goes up. In this study, it was also more likely for male twin siblings to both have a transgender identity than female twin siblings.

Many children who identify as the opposite gender begin to have a sense of this at a young age. For Levin, that’s another reason to believe there might be biological underpinnings. A 2015 study found that among 32 transgender children, each child had a strong, secure gender identity and didn’t express any signs of confusion.

But what may be the most likely biological driver of transgender identity, says Levin, are differences in hormone receptors.

“There’s long been the thought that since most of the differences we recognize between male and female are the result of prenatal hormone exposure,” says Levin. “A promising idea is that when particular areas of the brain develop, the receptor hormones may be flawed. For example, there may be parts of the brain that are unable to recognized testosterone in developing male bodies and therefore they are feminized.”

Levin firmly believes that the research conducted so far investigating the biological reasons behind transgender identity have been inconsistent in their results — yet those studies make sense on an intellectual level.

Nevertheless, she cautions that to definitively say, yes the cause of transgender identity can be biologically traced, is to discount the transgender experience of people who — when tested — may not reveal a biological connection.

“My fear,” she says, “is that if, in the end, we can claim that there is a genetic basis or hormonal basis — if one doesn’t have that gene or that hormone exposure but knows oneself to be trans, then that doesn’t mean you are any less trans than someone who does have it.

“I think this biological determinism is frightening. I do think there is a chance there is a biological component, but I have serious doubts to whether we’ll ever find it.”


How does pharmacogenomics work?

Drugs interact with your body in numerous ways, depending both on how you take the drug and where the drug acts in your body. After you take a drug, your body needs to break it down and get it to the intended area. Your DNA can affect multiple steps in this process to influence how you respond to the drug. Some examples of these interactions include

    Drug Receptors. Some drugs need to attach to proteins on the surface of cells called receptors in order to work properly. Your DNA determines what type of receptors you have and how many, which can affect your response to the drug. You might need a higher or lower amount of the drug than most people or a different drug.

  • Example: Breast Cancer and T-DM1. Some breast cancers make too much HER2, a receptor, and this extra HER2 helps the cancer develop and spread. The drug T-DM1 can be used to treat this type of breast cancer and works by attaching to HER2 on cancerous cells and killing them. If you have breast cancer, your doctor may test a sample of your tumor to determine if T-DM1 is the right treatment for you. If your tumor has a high amount of HER2 (HER2 positive), your doctor may prescribe T-DM1. If your tumor does not have enough HER2 (HER2 negative), T-DM1 will not work for you.

    Drug Uptake. Some drugs need to be actively taken into the tissues and cells in which they act. Your DNA can affect uptake of certain drugs. Decreased uptake can mean that the drug does not work as well and can cause it to build up in other parts of your body, which can cause problems. Your DNA can also affect how quickly some drugs are removed from the cells in which they act. If drugs are removed from the cell too quickly, they might not have time to act.

  • Example: Statins and Muscle Problems. Statins are a type of drug that act in the liver to help lower cholesterol. In order for statins to work correctly, they must first be taken into the liver. Statins are transported into the liver by a protein made by the SLCO1B1 gene. Some people have a specific change in this gene that causes less of a statin called simvastatin to be taken into the liver. When taken at high doses, simvastatin can build up in the blood, causing muscle problems, including weakness and pain. Before prescribing simvastatin, your doctor may recommend genetic testing for the SLCO1B1 gene to check if simvastatin is the best statin for you or to determine what dose would work best.

    Drug Breakdown. Your DNA can affect how quickly your body breaks down a drug. If you break the drug down more quickly than most people, your body gets rid of the drug faster and you might need more of the drug or a different drug. If your body breaks the drug down more slowly, you might need less of the drug.

  • Example: Depression andAmitriptyline. The breakdown of the antidepressant drug amitriptyline is influenced by two genes called CYP2D6 and CYP2C19. If your doctor prescribes amitriptyline, he or she might recommend genetic testing for the CYP2D6 and CYP2C19 genes to help decide what dose of the drug you need. If you breakdown amitriptyline too fast, you will need a higher dose for it to work, or you may need to use a different drug. If you breakdown amitriptyline very slowly, you will need to take a smaller dose or will need to take a different drug to avoid a bad reaction.
  • Targeted Drug Development. Pharmacogenomic approaches to drug development target the underlying problem rather than just treating symptoms. Some diseases are caused by specific changes (mutations) in a gene. The same gene can have different types of mutations, which have different effects. Some mutations may result in a protein that does not work correctly, while others may mean that the protein is not made at all. Drugs can be created based on how the mutation affects the protein, and these drugs will only work for a specific type of mutation.
    • Example: Cystic Fibrosis and Ivacaftor. Cystic fibrosis is caused by mutations in the CFTR gene which affect the CFTR protein. The CFTR protein forms a channel, which acts as a passageway to move particles across the cells in your body. For most people the protein is made correctly, and the channel can open and close. Some mutations that cause cystic fibrosis result in a channel that is closed. The drug ivacaftor acts on this type of mutation by forcing the channel open. Ivacaftor would not be expected to work for people with cystic fibrosis whose mutations cause the channel not to be made at all.

    Example: Cystic Fibrosis


    Cyclic Nucleotides

    Figure (PageIndex<1>): Cyclic Nucleotides

    Cyclic AMP (cAMP)

    Some of the hormones that achieve their effects through cAMP as a second messenger:

    Cyclic AMP is synthesized from ATP by the action of the enzyme adenylyl cyclase.

    • Binding of the hormone to its receptor activates
    • a G protein which, in turn, activates
    • adenylyl cyclase.
    • The resulting rise in cAMP turns on the appropriate response in the cell by either (or both):
      • changing the molecular activities in the cytosol, often using Protein Kinase A (PKA) &mdash a cAMP-dependent protein kinase that phosphorylates target proteins
      • turning on a new pattern of gene transcription

      Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects

      Caffeine is the most widely consumed central-nervous-system stimulant. Three main mechanisms of action of caffeine on the central nervous system have been described. Mobilization of intracellular calcium and inhibition of specific phosphodiesterases only occur at high non-physiological concentrations of caffeine. The only likely mechanism of action of the methylxanthine is the antagonism at the level of adenosine receptors. Caffeine increases energy metabolism throughout the brain but decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion. Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. Many of the alerting effects of caffeine may be related to the action of the methylxanthine on serotonin neurons. The methylxanthine induces dose-response increases in locomotor activity in animals. Its psychostimulant action on man is, however, often subtle and not very easy to detect. The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue. Caffeine exerts obvious effects on anxiety and sleep which vary according to individual sensitivity to the methylxanthine. However, children in general do not appear more sensitive to methylxanthine effects than adults. The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.