King Cheetah.

The king cheetah is a rare mutation of the cheetah characterized by a distinct fur pattern. The cause of this alternative coat pattern was found to be a mutation in the gene for transmembrane aminopeptidase Q, the same gene responsible for the striped ‘mackerel’  versus blotchy ‘classic’ patterning seen in tabby cats. The mutation is recessive and must be inherited from both parents for this pattern to appear, which is one reason why it is so rare.

Receptors intro - pharmacology

Drugs act at four different levels

  • Molecular - immediate target for most drugs (eg propanolol binds to B-adregenic receptors)
  • Cellular - biochemical and other consequent effects (eg propanolol reduces Ca2+)
  • Tissue - function altered (eg propanolol decreases myocardial contractility) 
  • System - function altered (eg propanolol reduces need for cardiac output, easing pressure on cardiovascular system)

Most drug targets are proteins 

  • Receptors - for transmitter substances and hormones
  • Enzymes
  • Transport systems - ion channels, active transport
  • Substrates
  • Second messengers 
  • Antibodies 

some drugs act on nucleic acids.


“Receptors are the sensing elements in the system of chemical communication that coordinate the function of all the different cells in the body.”

Upon recognition of ligand (chemical signalling molecule), receptor proteins transmit the signal into a biochemical change in the target cell.

Cell surface receptors

Hydrophilic transmitters act on cell surface receptors

  • peptides
  • most neurotransmitters 
  • other small molecules

All cell surface receptors are transmembrane proteins 

  • Extracellular domain - receptor site
  • transmembrane domain
  • intracellular domain - catalyic/coupling site, only present on certain receptors

Intracellular receptors 

Hydrophobic (lipid soluble) transmitters act on intracellular receptors

  • steroids
  • thyroid hormones
  • vitamin D

Drug interaction with receptors 

  • Agonist - activates receptor
  • Antagonist - binds to receptor without activating, thus presenting activation
  • Affinity - measure of how avidly a drug binds with receptor

Side effects occur when drugs bind to more than one type of receptor. Some bind irreversibly and most bind with weak intermolecular bonds. An equilibrium arises between bound and unbound drug.

(notes on types of receptor to follow - overview:)

Ligand-gated ion channels: open or close upon binding of a ligand

G-protein-coupled receptors: Transmembrane receptor protein that stimulates a GTP-binding signal transducer protein (G-protein) which in turn generates an intracellular second messenger

Nuclear receptors: Lipid soluble ligand that crosses the cell membrane and acts on an intracellular receptor

Kinase-linked receptors: Transmembrane receptor proteins with intrinsic or associated kinase activity which is allosterically regulated by a ligand that binds to the receptor’s extracellular domain


Cell Signaling 
Requested by oceanliquidation
(Cliffnotes AP Biology Workbook 4th Edition)

Please note there are 2 more types of signal receptors: 
Protein Kinase Receptors: transmembrane-protein enzymes that are kinases, that add a phosphate group to  protein. The best understood of these are Receptor Tyrosine Kinases.
Intracellular Receptors: receptors positioned in the cytoplasm or nucleus, and are able to pass through the phospholipid membrane. 


Been doing some more oncology research to add to my thermotherapy extension (a paper I am aiming to publish/write for my uni interviews based on thermotherapy and nanoparticles) Hope you find it interesting! Remember, 20% OF BREAST CANCER PATIENTS fall under the HER2 subtype…

The ErbB family consists of four plasma membrane-bound receptor tyrosine kinases. One of which is erbB-2, and the other members being epidermal growth factor receptor, erbB-3 (neuregulin-binding; lacks kinase domain), and erbB-4. All four contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular domain that can interact with a multitude of signaling molecules and exhibit both ligand-dependent and ligand-independent activity. Notably, no ligands for HER2 have yet been identified. HER2 can heterodimerise with any of the other three receptors and is considered to be the preferred dimerisation partner of the other ErbB receptors.

Dimerisation results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways.

Signaling pathways activated by HER2 include:

  • mitogen-activated protein kinase (MAPK)
  • phosphoinositide 3-kinase (PI3K/Akt)
  • phospholipase C γ
  • protein kinase C (PKC)
  • Signal transducer and activator of transcription (STAT)

In summary, signaling through the ErbB family of receptors promotes cell proliferation and opposes apoptosis, and therefore must be tightly regulated to prevent uncontrolled cell growth from occurring.

GPCRs/7-transmembrane receptors (7TM receptors)

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

Main targets:

  • 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.

(notes on these coming soon)

CFTR (cystic fibrosis transmembrane conductance regulator) protein expression in well-differentiated human bronchial epithelial cultures. Well-differentiated cultures derived from human bronchial epithelial tissues were immunostained with CFTR and tubulin antibodies and analyzed on a Leica SP2 laser confocal microscope. The image represents an overlay of the DIC (grayscale), CFTR (red), cilia (tubulin, green), and nuclei (DAPI, blue) confocal planes, and depicts an epithelial cell sheet that contains a group of ciliated cells surrounding a goblet cell (bottle-shaped cell with no cilia). CFTR is expressed only at the apical membrane of ciliated cells, but not goblet cells. Magnification x190. Reproduced from Kreda et al 2005 Miol Biol Cell 16, 2154 with permission of ASCB / MBC.

The CFTR protein functions as a channel across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. The channel transports chloride ions into and out of cells. The transport of chloride ions helps control the movement of water in tissues, which is necessary for the production of thin, freely flowing mucus. Mucus is a slippery substance that lubricates and protects the lining of the airways, digestive system, reproductive system, and other organs and tissues.

More than 1,000 mutations in the CFTR gene have been identified in people with cystic fibrosis. The resulting abnormal channel breaks down shortly after it is made, so it never reaches the cell membrane to transport chloride ions and the movement of water into and out of cells.

As a result, cells that line the passageways of the lungs, pancreas, and other organs produce mucus that is abnormally thick and sticky. The abnormal mucus obstructs the airways and glands, leading to the characteristic signs and symptoms of cystic fibrosis.

Action waves in the brain

A new theoretical model describes the nervous impulse as an electromechanical wave

Two researchers from Princeton University have developed a theoretical model describing the nervous impulse as an electromechanical wave that travels along nerve fibres, explaining curious experimental observations and challenging basic assumptions about how the brain works. The mechanism of the nervous impulse was made clear in a series of experiments carried out by Alan Hodgkin and Andrew Huxley from the late 1930s onwards. They prepared segments of giant squid axon, placed them in salt water solution, and then impaled them with microelectrodes, with which they could both inject electrical current into the fibre and record its voltage. This enabled them to control the voltage across the membrane and also measure the movements of current responsible for producing the impulse. Resting nerve cells have a lower concentration of sodium ions, and a higher concentration of potassium ions, than the spaces surrounding them, so that the inside of the membrane is negatively charged with respect to the outside. This transmembrane voltage is called the resting potential; most nerve cells have a resting potential of about -70 millivolts. Hodgkin and Huxley discovered that the nervous impulse is caused by the flow of sodium ions into the cell, followed almost immediately by the flow of potassium ions out. The ions move in and out through channel proteins that traverse the membrane, and open briefly in response to changes in membrane voltage, allowing first one ion species in, then the other out, in just one thousandth of a second. The influx of sodium ions reverses the transmembrane voltage, but then the potassium ion efflux quickly reverts it to its resting state. Hence, neuroscientists refer to nervous impulses as action potentials.

(via Action waves in the brain | Science | The Guardian)

Uncovering the 3D structure of a key neuroreceptor

Neurons are the cells of our brain, spinal cord, and overall nervous system. They form complex networks to communicate with each other through electrical signals that are generated by chemicals. These chemicals bind to structures on the surface of neurons that are called neuroreceptors, opening or closing electrical pathways that allow transmission of the signal from neuron to neuron. One neuroreceptor, called 5HT3-R, is involved in conditions like chemotherapy-induced nausea, anxiety, and various neurological disorders such as schizophrenia. Despite its clinical importance, the exact way that 5HT3-R works has been elusive because its complexity has prevented scientists from determining its three-dimensional structure. Publishing in Nature, EPFL researchers have now uncovered for the first time the 3D structure of 5HT3-R, opening the way to understanding other neuroreceptors as well.

Neuroreceptors: structure and function
Communication between the neurons of our body is mediated by neuroreceptors that are embedded across the cell membrane of each neuron. Neuronal communication begins when a neuron releases a small molecule, called a ‘neurotransmitter’, onto a neighboring neuron, where it is identified by its specific neuroreceptor and binds to it. The neurotransmitter causes the neuroreceptor to open an electrically conducting channel, which allows the passage of electrical charge across the neuron’s membrane. The membrane then becomes electrically conducting for a fraction of a millisecond, generating an electrical pulse that travels across the neuron. The family of neuroreceptors that work in this way is widespread across the nervous system, and is referred to as the “ligand-gated channel” family.

The mystery is how the binding of the neurotransmitter can induce the opening of an electrical channel to transport a signal into the neuron. The understanding of these molecular machines is of great medical importance, especially since neuroreceptors are involved in many neurological diseases. Currently, none of the mammalian ligand-gated channel neuroreceptors have been structurally described, which significantly limits our understanding of their function on a molecular level.

Uncovering the structure of 5HT3-R
The team of Horst Vogel at EPFL has used X-ray crystallography to determine the 3D structure of a representative ligand-gated channel neuroreceptor, the type-3 serotonin receptor (5HT3-R). This neuroreceptor recognizes the neurotransmitter serotonin and opens a transmembrane channel that allows electrical signals to enter certain neurons. The 5HT3 receptor was grown in and then isolated from human cell cultures, and finally crystallized.

But before obtaining the 5HT3-R crystals, the EPFL team had to overcome a number of challenges. First, the relatively large size of the membrane-embedded 5HT3-R, like that of other similar channel neuroreceptors, makes it notoriously difficult to purify in sufficient quality and quantity. After years of painstaking work, the EPFL scientists succeeded in obtaining a few milligrams of 5HT3-R, which was still not enough to grow crystals using conventional methods.

Still, the crystal quality was insufficient. To address this, Vogel’s team used small antibodies, so-called nanobodies, which were obtained from llamas after the animals were injected with purified 5HT3-R. From a large library of isolated nanobodies, a particular one was found to form a stable complex with the 5HT3-R, and this complex eventually yielded crystals of exceptional quality.

After this, the procedure was straightforward: The crystals for X-ray crystallography were investigated at the synchrotron facilities at the Paul Scherrer Institut in Villigen and the European facilities in Grenoble. In this well-established technique, the crystals diffract X-rays in a characteristic pattern from which the 3D structure can be reconstructed.

The X-ray diffraction experiments yielded the 3D structure of 5HT3-R at an unprecedented resolution of 3.5 Ångstroms (3.5 millionths of a millimeter). The resulting 3D image shows a bullet-shaped 5HT3 receptor with its five subunits symmetrically arranged around a central water-filled channel that traverses the neuron’s cell membrane. The channel can adopt two states: a closed, electrically non-conducting state or, after binding a neurotransmitter, an open, electrically conducting state that allows the flow of electrical charges in and out of the neuron to generate an electrical signal.

“We have now elucidated the molecular anatomy of a receptor that plays a central role in neuronal transmission,” says Horst Vogel. “It is the first 3D structure of its kind and may serve as a blueprint for the other receptors of this family. In the next step, we have to improve the resolution of the structure, which might give us information on how to design novel medicines that influence this neuroreceptor’s function.”