SONGLyrical DNA
Move Left, Move Right
A song about cell signaling. The lyrics follow a peptide hormone from its release by an endocrine cell, through the blood to a receptor on a target cell, along a relay of G protein, cAMP and PKA that amplifies the message, to new genes being transcribed and a new protein being made and secreted, and finally to how the signal is blocked and switched off. Select any highlighted line to see the biology behind it.
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Interactive lyrics
Lines with a dotted underline and a + marker have an explanation. Select one and the science appears beside the lyrics. Everything else is ordinary lyric text.
Intro
Tiny message.
Big reaction.
Feel the switch.
Put it in motion.
Hook
Move left, move right,
Move left, move right,
Move left, move right,
Move left, move right,
Verse 1
Build
Bind it.
Switch it.
Relay it.
Amplify.
Drop
Move left, move right,
Move left, move right,
Left, left—pass it on.
Right, right—pass it on.
Move left, move right,
Verse 2
Verse 3
Ribosome ready, let the code say more.
New protein message out into the street.
Break
Final drop
Move left, move right,
Move left, move right,
Left, left—pass it on.
Right, right—pass it on.
Move left, move right,
Outro
Signal received.
Message relayed.
A whole new response
From a little change.
Concepts covered
Reception and amplificationThe hook sums up the whole pathway. The signaling molecule outside the cell touches only the outer part of its receptor, yet the receptor changes shape and switches on proteins inside the cell. Several steps in the relay are enzymes, and each active enzyme acts on many molecules, so a few hormone molecules can produce a large response. Left and right are dance cues, not directions the signal travels.
Endocrine signaling and exocytosisThe signal starts in an endocrine cell, which stores a peptide hormone inside vesicles. When the cell is stimulated, a vesicle's membrane fuses with the plasma membrane and empties the hormone outside the cell, a process called exocytosis. In endocrine signaling the hormone enters the blood, which carries it throughout the body, but only cells with a matching receptor respond. Glucagon is a peptide hormone that travels and signals this way.
Ligand recognitionA peptide hormone is an amino acid chain, too large and water-soluble to cross the bilayer, so its receptor sits in the plasma membrane with its binding site facing out. The hormone is the ligand: only receptors with a matching binding site can bind it. Binding changes the receptor's shape, and the change reaches its inner side, which can now act on proteins inside the cell. The hormone itself stays outside. Steroid hormones, by contrast, cross the membrane and bind receptors inside the cell.
G protein activationThe receptor here is a G protein-coupled receptor, or GPCR. On the inner side of the membrane it meets a G protein, which is off while it holds GDP. The changed receptor makes the G protein release GDP and pick up GTP, which switches it on. The alpha subunit, now carrying GTP, separates from the other subunits and passes the signal to the next protein in the relay. Holding GTP means on and holding GDP means off, which is why the song calls it a nucleotide switch.
Second messengers and amplificationThe active alpha subunit binds adenylyl cyclase, an enzyme in the plasma membrane, and turns it on. Adenylyl cyclase converts ATP into cyclic AMP, or cAMP, and keeps making it for as long as it stays active, so one enzyme produces many cAMP molecules and the signal grows. cAMP is a second messenger: a small molecule that spreads through the cytoplasm and carries the signal from the membrane to proteins inside the cell. Here it switches on protein kinase A, or PKA.
Protein phosphorylationPKA is a kinase, an enzyme that moves a phosphate group from ATP onto other proteins. The P in the lyric is that phosphate. Adding it, called phosphorylation, adds negative charge and changes the target protein's shape, which can switch the protein on or off depending on what it is. One active PKA phosphorylates many targets, another step that amplifies the signal. Different cells contain different targets, so the same cAMP signal can produce different responses in different tissues.
Changes in gene expressionSome responses come within seconds, when enzymes already in the cytoplasm are phosphorylated and change their activity. Others take longer because they change gene expression. In this pathway, active PKA can enter the nucleus and phosphorylate a transcription factor, a protein that binds DNA and helps start transcription of particular genes. More transcription of those genes means more of the protein they code for. Other signals turn genes down instead, which is also a response.
Transcription and mRNA exportIn a eukaryotic cell the DNA stays inside the nucleus, and the gene's message leaves as RNA. RNA polymerase reads one strand of the DNA as a template and builds a complementary RNA. That first transcript is processed before it leaves, and the finished messenger RNA, or mRNA, passes through a nuclear pore into the cytoplasm. One gene can be transcribed many times, so many mRNA copies can carry the same message to the ribosomes.
TranslationA ribosome reads the mRNA three nucleotides at a time. Each group of three is a codon, and the letters are the bases A, U, G and C. A transfer RNA, or tRNA, has an anticodon that pairs with one codon and carries the amino acid that codon specifies. The ribosome links each new amino acid to the growing chain, then moves on to the next codon. Reading continues until a stop codon, so the order of codons sets the order of amino acids in the protein.
The secretory pathwayA protein made for export starts on a free ribosome, but a signal at the front of the new chain sends that ribosome to the rough endoplasmic reticulum, and the protein is threaded into the ER as it is made. There it folds. Vesicles carry it to the Golgi, which modifies and sorts it and packs it into a new vesicle bound for the plasma membrane. When that vesicle fuses with the membrane, exocytosis releases the protein outside the cell, the same step that released the hormone at the start.
Competitive receptor inhibitionA signal can be stopped at the first step. One kind of receptor blocker, a competitive antagonist, fits the same binding site as the normal ligand but does not change the receptor's shape the way the ligand does, so no G protein is switched on. While the blocker occupies the site, the hormone cannot bind there. Because blocker and ligand compete for one site, more ligand can outcompete the blocker. Beta blockers slow the heart this way at receptors for adrenaline.
Turning a signal offA signal has to stop as well as start, or the cell would keep responding long after the hormone was gone. The alpha subunit switches itself off by breaking down its GTP to GDP, so it stops activating adenylyl cyclase. Other enzymes break down cAMP, so PKA returns to its inactive form, and still others remove the phosphates PKA added. Once the hormone leaves the receptor, the whole relay resets and is ready for the next message.
