New role of cholesterol in regulating brain proteins discovered
A study led by researchers at the Hospital del Mar Medical Research Institute (IMIM) and the Institute of Medical Physics and Biophysics at the Faculty of Medicine in Charité Hospital, Berlin, published in the journal Nature Communications, demonstrates that the
cholesterol present in cell membranes can interfere with the function
of an important brain membrane protein, through a previously unknown
mode of interaction. Specifically, cholesterol is capable of
regulating the activity of the adenosine receptor, by invading it and
accessing the active site. This will allow new ways of interacting with
these proteins to be devised that in the future could lead to drugs for
treating diseases like Alzheimer’s.
The adenosine receptor belongs to the GPCR family (G Protein-Coupled
Receptors), a large group of proteins located in cell membranes, which
are key in the transmission of signals and communication between cells.
GPCRs are therefore involved in the majority of important physiological
processes, including the interpretation of sensory stimuli such as
vision, smell, and taste, the regulation of the immune and inflammatory
system, and behaviour modulation.
“Cholesterol is an essential component of neuronal membranes,
where GPCRs reside along with other proteins. Interestingly, the levels
of cholesterol in the membrane are altered in diseases such as
Alzheimer’s, where GPCRs like the adenosine receptor play a key role”, explains Jana Selent, head of the GPCR Drug Discovery research group at the GRIB, a joint programme between Hospital del Mar Medical Research Institute (IMIM) and Universitat Pompeu Fabra (UPF). “This
study has shown that cholesterol can exert direct action on this
important family of proteins in neuronal membranes, the GPCRs, and
establishes the basis for a hitherto unknown interaction pathway between
the cell membrane and proteins”, adds the researcher.
Up to now, it was thought that membrane cholesterol could regulate
the activity of these proteins through two mechanisms: either by
altering the physical properties of the membrane, or by binding to the
surface of the protein. In both cases, it was thought that cholesterol
could only exercise its modulatory action from outside the protein.
However, by using latest-generation molecular simulations the
researchers were able to detect the fact that cholesterol can leave the
neuronal membrane and get within the adenosine receptor, in particular
accessing the receptor’s active site. With this information, and in
collaboration with Dr. Mairena Martin and Dr. José L. Albasanz from the University of Castilla-La Mancha,
we designed an experimental protocol using cell assays to demonstrate
that cholesterol is able to modulate the activity of this receptor by
accessing its interior.
“Cholesterol levels in cell membranes could have a more
direct effect than previously thought on the behaviour of key proteins
in central nervous system diseases. In particular, high levels of
membrane cholesterol like those present in Alzheimer’s patients probably
block the adenosine receptor, which could in turn be related to certain
symptoms observed in this disease”, explains Ramón Guixà González, a postdoctoral researcher at the Institute of Medical Physics and Biophysics at the Faculty of Medicine in Charité Hospital in Berlin and first author of the article. “Although
other studies are needed to prove this relationship, this work provides
key knowledge that could be used in the future in the development of
new molecules that, like cholesterol, have the ability to get inside the
receptor and modulate its activity”, says the researcher.
The results from this study represent a paradigm shift in the
relationship between membrane cholesterol and GPCRs in the central
nervous system, and open up new avenues of research in fields where the
cholesterol-GPCR relationship is essential. It also appears that the
cholesterol access pathway into the receptor is an evolutionary
footprint. It is therefore necessary to discover whether the molecular
mechanism described in this paper is present in other GPCRs and
therefore potentially involved in a wide range of central nervous system
So, today I learned that “G-proteins”, named after the guanine nucleotides they bind to, act as molecular switches inside cells, and “heterotrimeric” G proteins are activated by G protein-coupled receptors. These G-proteins consist of alpha, beta and gamma subunits. G-alpha subunits, when inactivated, do some shit that I am too tired to explain.
I also discovered that I have a half decent view of a sunset from the library.
To those who were waiting yesterday for this post, I’m extremely sorry. For some reason I Thought yesterday was sunday -____- but here it is.
reflex tachycardia caused by nitrate can be prevented by administering beta adrenergic blockers w
prazosin- selective alpha 1 adrenergic blocking medication used for HTN and BPH
hydrochlorothiazide is a weak diuretic
phenylephirine is an alpha agonist which is classified as a vasopressor agent. Its used in cases of shock and severe hypotension
hydralazine is a direct acting arteriolar dilator . It causes a reflex tachycardia which can also be prevented with administering beta blocker
ataxia telangiectasia an autosomal recessive d/o characterized by DNA hypersensitivity to ionizing radiation. Cerebellar atrophy leads to ataxia that occurs in first years of life. . Patients with ataxia telangiectasia also have sever immunodeficiency with repeated sinopulmonary infections. This risk of cancer in these patients in increased significantly b/c of inefficient DNA repair
XP is characterized by DNA hypersensitivity to UV radiation causing premature skin agin and increased risk of skin cancer (malignant melanoma and squamous cell carcinoma)
Fanconi anemia is caused by hypersensitivity of DN TO CROSS LINKING AGENTS
Bloom syndrome is characterized by generalized chromosome instability. Increased susceptibility to neoplasms is present
HNPCC d/t to defect in DNA mismatch repair enzymes leading to increased susceptibility to colon cancer
caudate nucleus atrophy- huntington dz
Lewy bodies- Parkinsonism
loss of neurons in substantia nigra- Parkinson’s dz
neurofibrillary tangles in neocortex – Alzheimer’s dz
double vision while walking down the stairs or while reading the newspaper- palsy of cranial nerve 4 (trochlear nerve)
optic nerve (CN2) transmits visual info to brain damage causes loss of vision
CN3 occulomotor nerve innervates superior rectus medial rectus inferior rectus and inferior oblique. Which all collectively perform most ye movement. Palsies of this nerve can cause vertical and horizontal diplopia and an enlarged nonreactive pupil
abducens nerve CN6 innervates lateral rectus which is responsible for abdcution of eye. Palsy of this nerve can cause horizontal diplopia and inward deviation ( inward deviation)
MLF lesion a/w internuclear ophthalmoplegia, which presents with impaired horizontal eye movement and weak adduction of affected eye with simultaneous abduction nystagmus of contralateral eye
at low doses atenolol is a selective beta 1 adrenergic antagonist . Beta 1 receptors are found in cardiac tissue and on renal juxtaglomerular cells but not on vascular smooth muscle. The beta 1 receptor is G protein coupled receptor a/w Gs G protein which increases cAMP levels. Blockage of beta receptor therefore means decreased cAMP levels in cardia and renal tissue without affecting cAMP levels in vascular smooth muscle
pure red cell aplasia is a rare form of marrow failure characterized by sever hypoplasia of marrow erythroid elements in setting of normal granulopoiesis and thrombopoiesis. Pure red cell aplasia is a/w thymoma lymphocytic leukemias and parvovirus B19 infections
deficiency of 21 hydroxylase is MC type of CAH. . These patients present with cortisol and aldosterone deficiency combined with androgen excess.. genitalia of females infants may be masculinized to some degree; male infants however are normal in appx
When asked a question regarding DKA know that ph is decreased H2PO4 is increased (it is titratable acid) and also bicarbonate excretion is decreased. This response is overtime meaning these changes are made because of the acidosis that the patient has . Therefore in order to fix metabolic acidosis d/t DKA bicarbonate excretion is decreased and urinary ph is decreased and titratable acid excretion is increased.
Musculocutaneous nerve innervates flexor muscles of upper arm and provides sensory innervation to lateral forearm. Musculocutaneous nerve is derived from upper trunk of brachial plexus and can be injured by forceful injuries that cause separation of neck and shoulder. It is derived from C5-C7 ventral rami
posterior arm and forearm are both innervated by the branch of the radial nerve which is posterior cutaneous nerve of the arm and posterior cutaneous nevre of the forearm
thenar eminence is innervated by recurrent branch of median nerve
g6pd deficiency – cant convert glucose 6 phosphate to 6 phosphogluconate . G6Pd requires NadPH as a cofactor to work
urine sample turned black= alkaptonuria which is an autosomal recessive d/o in which lack of homogentisic oxidase blocks the metabolism of phenylalanine and tyrosine at the level of homogentisic acid leading to accumulation of homogentisic acid. Turns black because homogentisic acid excreted in urine undergoes oxidation when exposed to oxygen in air
alkaptonuria cause ochronosis a blue black pigment evident in ears nose and cheeks
conversion of phenylalanine to tyrosine is defective in PKU and usually occurs d/t defect in phenylalanine hydroxylase
small percentage of PKU cases are also d/t dihydrobiopterin reductase deficiency
branched chain a.a. Are valine isoleucine and leucine
blastomyces dermatidis is a dimorphic fungus that is seen in tissue as round yeasts with doubly refractive walls and broad based budding. Endemic to great lakes and ohio and Mississippi river regions, present in soil and rotten organic matter
blastomyces mold form (branching hyphae) predominates in environment with average temperature 25-30 degrees Celsius. In the human body it assumes yeast form (single cells)
blastomyces in lungs assumes yeast form and induces granulomatous response
aspergillus fumigatus causes lung dz in immunocompromised and only has a mold form . It is seen as septate hyphae that branch at 45 degrees (angle)
oppotunistic mold with irregular non septate hyphae that branch at wide angles (>90)= mucor and rhizopus
starts with just a sinus infection and then you end up getting a rapid infection to the brain because this organism can penetrate the cribriform plate causing frontal lobe abscess – Mucor and rhizopus
cryptococcus neoformans can also cause lung dz but in addition causes meningitis in immunocompromised and in contrast to blastomycosis it forms narrow based buds and has thick polysaccharide capsule which stains with india ink
histoplasma capsulatum causes lung dz and is also a dimorphic fungus like blastomyces but the yeast form of histoplasma is found intracellularly within macrophages
coccidioides immitis is also a dimorphic fungus but is seen as spherules (round encapsulated structures containing many endospores) in tissue sample, barrel shaped arthroconidia a/w dust storms which causes San Joaquin Valley fever (inhalation of dust particles)
G-protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in eukaryotes.
single polypeptide chain comprising of seven transmembrane α-helices
extracellular N-terminal domain of varying length,
intracellular C-terminal domain.
length of the extracellular N terminus and the location of the agonist binding domain determines family.
The long, third cytoplasmic loop couples to the G-protein
Usually particular receptor subtypes couple selectively with particular G-proteins
For small molecules, such as noradrenaline, the ligand-binding domain of class A receptors is buried in the cleft between the α-helical segments within the membrane. Peptide ligands bind more superficially to the extracellular loops
G protein system
GPCRs interact with G proteins in the plasma membrane when an external signaling molecule binds to a GPCR, causes a conformational change in the GPCR.
G-proteins comprise a family of membrane-resident proteins whose function is to recognise activated GPCRs and pass on the message to the effector systems that generate a cellular response.
G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP).
The G proteins that associate with GPCRs are heterotrimeric, (alpha beta and gamma subunits)
alpha and gamma are attached to the plasma membrane by lipid anchors
Trimer in resting state
activated alpha monomer and beta/gamma dimer
Guanine nucleotides bind to the α subunit, which has enzymic activity,catalysing the conversion of GTP to GDP. The β and γ subunits remain together as a βγ complex. All three subunits are anchored to the membrane through a fatty acid chain, coupled to the G-protein through a reaction known as prenylation.
G-proteins are freely diffusible so a single pool of G-protein in a cell can interact with several different receptors and effectors
When GPCR is activated by an agonist, a conformational change causes it to acquire high affinity for αβγ (G protein)
bound GDP dissociates and is replaced with GTP, which in turn causes dissociation of the G-protein trimer, releasing α-GTP and βγ subunits - the ‘active’ forms of the G-protein
which diffuse in the membrane and can associate with various enzymes and ion channels
Signalling is terminated on hydrolysis of GTP to GDP through the GTPase activity of the α subunit.
resulting α–GDP dissociates from the effector, and reunites with βγ
Attachment of the α subunit to an effector molecule increases its GTPase activity
GTP hydrolysis is termination –> activation of the effector tends to be self-limiting
Second messenger targets for G proteins
Adenylyl cyclase (responsible for cAMP formation)
Phospholipase C (inositol phosphate and diacylglycerol (DAG) formation)
Ion channels, particularly calcium and potassium channels
Rho A/Rho kinase (system controlling the activity of many signalling pathways for cell growth and proliferation, smooth muscle contraction, etc.)
Mitogen-activated protein kinase (MAP kinase) system controlling cell functions eg division.