Signals and How Far They Travel

In January 1902, two London physiologists cut every nerve running to a loop of a dog’s small intestine and dripped weak acid onto its lining. The pancreas, in a different part of the abdomen, began to secrete anyway. With no wire between the two organs, what carried the message?

The answer was a chemical. That answer shapes this whole course, because every cell is sealed inside a membrane and learns about the world only from what reaches its surface. This lesson asks two things first: how far does a signal travel, and what does that distance cost?

The problem: a cell cannot see past its own surface

Two terms first. Signal transduction is the process by which a cell converts a signal from outside into a change inside, in its behavior or in the genes it reads. A first messenger is the signal itself, the molecule or physical stimulus that arrives from outside before the cell has done anything with it. (The overview lesson signal-transduction follows one signal’s relay inside the cell. This lesson stays outside.)

Back to the dog. The leading view in 1902, held by Ivan Pavlov among others, was that the gut instructed the pancreas by nerve. Nerves are fast and measurable, and they accounted for everything anyone had seen. To get past that view, someone had to take the nerves out and still watch the pancreas answer. William Bayliss and Ernest Starling did that on 16 January 1902 at University College London. The same afternoon they cut off a further piece of intestine, rubbed its lining with sand in weak acid, filtered the liquid and injected it into a vein. The pancreas secreted even more.

Cutting the nerves left one road from gut to pancreas, and that road was the blood. Something in the gut lining, later named secretin, was released by acid and carried to the pancreas. The injection made the point harder to escape. The extract went everywhere the blood goes, so every organ was exposed to it, and the pancreas was the one that answered with juice. A signal does not choose its audience. The receiver does.

Otto Loewi showed the same logic across a much shorter gap. In 1921 he stimulated the vagus nerve of a beating frog heart, which slowed it, then took the salt solution that had been in contact with that heart and transferred it to a second heart. The second heart slowed too, though no nerve to it had fired. He called the unknown substance Vagusstoff, vagus substance. A nerve cell had given an order by releasing a chemical that drifted to its target. The chemical was later identified as acetylcholine.

The idea: five distances, each with its own bargain

Every signal sits somewhere on a ruler of distance. The five positions below differ in speed, in reach and in how the message avoids the wrong cell. Real tissues show lots of mixing and matching of signaling types, so treat these as a vocabulary.

Contact. Two cells touch, and nothing is released into the space around them. In juxtacrine signaling, a ligand (a molecule that binds a receptor) is anchored in one cell’s membrane and binds a receptor on the cell pressed against it. The message reaches exactly one neighbor, and the contact is the address. In a gap junction, protein channels link the interiors of two cells, and ions and small molecules pass straight through.

Autocrine. The cell releases a signal that binds receptors on its own surface, which lets a cell reinforce its own decision.

Paracrine. The signal is released into the fluid between cells and acts on neighbors a short way off. Histamine released during inflammation is the standard example. The reach is short because the signal is diluted as it spreads and is destroyed or captured along the way.

Synaptic. A neuron releases a neurotransmitter into a gap only tens of nanometers wide, and the receiving cell sits right across it. This is a paracrine signal with the geometry built for speed and privacy: the distance is so small that the message arrives almost at once, and almost none of it reaches anyone else.

Endocrine. A gland releases a hormone, a signal carried in the blood, and every cell the blood reaches is exposed to it. Insulin and estradiol work this way.

Why so many modes? Because diffusion punishes distance. The typical time for a molecule to wander a distance x is:

t ≈ x² / 2D

Here D is the diffusion coefficient, about 10^-5 cm²/s for a small molecule in water. Time grows with the square of the distance. A small molecule crosses a 20 nm synaptic gap in a fraction of a microsecond, a millimeter in about eight minutes, and a centimeter in about fourteen hours. Past a millimeter or so, diffusion cannot deliver a message that has to act within a minute. That is why hormones ride the blood, which circulates around the body in about a minute, and why fast local signals need the gap to be tiny.

What counts as a signal: six kinds of first messenger

First messengers range from a push on the membrane to a whole protein. The list runs roughly from small to large:

• Physical stimuli: mechanical force, sound, temperature and light.
• Ions and small molecules: Ca2+, Na+, Cl-, O2, CO2, CO and NO.
• Metabolites: glucose, adenosine, lipids and amino acids.
• Hormones: estradiol and ghrelin, which are a steroid and a peptide.
• Secreted proteins: interleukins, growth factors, death factors and chemokines.
• Extracellular matrix: collagen, elastin, fibronectin and laminin.

The first question to ask about any of them is whether it can cross the membrane, because the answer decides where its receptor must be. The lipid core of the bilayer admits small molecules without charge and fat-soluble ones. O2, CO2 and NO slip through, and so does estradiol, a steroid built from four fused carbon rings with almost no charged groups. These can meet a receptor inside the cell.

Everything else must be read at the surface. Ions are charged and cannot pass. Neither can glucose, a peptide, a protein or a matrix fiber. Acetylcholine and epinephrine are small, but the nitrogen of acetylcholine carries a permanent positive charge, and the amine of epinephrine is positively charged at body pH. How surface receptors are built is the subject of lesson 4.

Why have a system that affects all systems at a distance?

Put the question to the endocrine system directly: isn’t it dangerous to release a molecule that touches every tissue? It would be, if the signal decided who responds. It does not.

The receptor, not the signal, sets who responds. The extract in the dog reached every organ, yet the pancreas was the one that secreted. The same holds inside one body. Epinephrine, a hormone from the adrenal gland, drives glycogen breakdown in liver cells, fat breakdown in fat cells and a stronger beat in the heart, and a cell without the receptor ignores it. Acetylcholine slows the heart and contracts skeletal muscle, because the two cell types carry different receptors for the same molecule. A signal is a word. What happens depends on who can read it.

Dilution and half-life set how long and how far. A hormone released into about five liters of blood is diluted at once, and it does not last: epinephrine and insulin each fall to half their level in the blood within minutes. The message fades unless the gland keeps sending it. Short-range signals work the same way on a smaller scale. A signal destroyed after a lifetime τ travels about:

reach ≈ √(D × τ)

A secreted protein diffuses in water with D near 10^-6 cm²/s, and measured values in tissue are lower, from about 10^-9 to 5 × 10^-7 cm²/s, so take 10^-6 as an upper bound. With it, a lifetime of 100 seconds gives a reach of about 100 µm, a few cell diameters. A lifetime of three hours stretches the reach to about a millimeter. A paracrine signal stays local because its neighborhood destroys or captures it quickly.

That points to a failure mode. Disrupting paracrine control is one route to cancer. A growth signal made safe by its short reach and short life becomes dangerous when a cell begins to answer its own call, or when the factor stops being cleared and its reach grows.

Stopping the message: clearance

A signal that cannot end is a switch stuck on. Cells end signals by clearing them: enzymes destroy the molecule, transporters pump it back into the cell that released it, or blood flow and diffusion carry it off.

Acetylcholine shows the fastest case. Acetylcholinesterase, an enzyme in the gap between nerve and muscle, destroys acetylcholine within about a millisecond of release. The speed is the point. If the transmitter lingered, the next message could not be told apart from the last, so the gap has to be wiped clean after every impulse.

That same speed made acetylcholine almost impossible to catch. By the time fluid from around a stimulated nerve reached a test tube, the enzyme had destroyed the transmitter, and what was left was far below anything a chemical test of the 1930s could detect. Loewi had shown in 1926 that eserine, a drug that blocks the enzyme, protects the transmitter, and eserine also makes a strip of leech muscle respond to far smaller amounts. In 1934 Henry Dale and Wilhelm Feldberg combined the two. The height of its twitch, read against twitches from known amounts, became the measurement. Fluid collected from a stomach while its vagus nerve was stimulated made the muscle contract. A nerve had been caught releasing the chemical.

Many transmitters are cleared another way. Serotonin is pumped back into the sending neuron by a transporter protein. A selective serotonin reuptake inhibitor (SSRI), such as fluoxetine, blocks that transporter, so serotonin stays in the synaptic gap longer and keeps its receptors occupied longer. That is the basis of its use against depression. Blocking acetylcholinesterase prolongs acetylcholine in the same way, which is why some Alzheimer’s drugs and nerve agents both act on this enzyme.

Design problem

You must tell every liver cell in the body to release glucose within a minute, and separately tell only the cell next door to divide. Choose a mode of signaling for each job and defend it.