A Gradient of Ten Thousand to One
At rest, the interior of a nerve cell holds very little free calcium, measured in nanomoles per liter. The fluid surrounding the cell, by contrast, carries levels in the millimolar range. The difference is no accident; it is kept up around the clock. Pumps in the cell membrane (PMCA), exchangers that swap calcium for sodium (NCX) and stores in the endoplasmic reticulum keep clearing the ion out of the cytoplasm.
This steep gradient has a practical payoff. Once a channel opens, a few thousand ions are enough to lift the level right next to the pore many times over. A small event is thereby turned into a signal that is easy to read.
| Where measured | Typical level | Side note |
|---|---|---|
| Cytoplasm at rest | 50–100 nmol/L | kept low by pumps and binding proteins |
| Blood plasma, ionized fraction | 1.1–1.3 mmol/L | held within narrow limits by hormones |
| Cerebrospinal fluid | about 1.0–1.2 mmol/L | bathes the synapses of the brain |
| Right at an open pore | 10–100 µmol/L and above | lasts only fractions of a millisecond |
Where the Calcium in the Blood Comes From
The ionized calcium level in the blood hardly moves over the course of a day. Parathyroid hormone and calcitriol see to it that uptake from the gut, excretion through the kidneys and drawing on the body’s own reserves stay in step. Food provides the fresh supply. For adults, the EU reference intake of 800 mg per day is set by Regulation (EU) No 1169/2011.
| Serving size | Calcium, rounded |
|---|---|
| Emmental cheese, 30 g | approx. 310 mg |
| Milk, 200 ml | approx. 240 mg |
| Kale, cooked, 150 g | approx. 200 mg |
| Mineral water with more than 150 mg/L, 0.5 L | at least 75 mg |
Channel Pores at the Active Zone
The spot in the terminal where vesicles loaded with messenger wait in readiness is called the active zone. Electron micrographs reveal a dense protein lattice there, with the calcium channels set into it. These belong to the family of voltage-gated channels and open as soon as the membrane depolarizes.
Cav2.1 and Cav2.2 Side by Side
Pharmacologists first told the channel types apart with the help of toxins: omega-agatoxin, taken from the venom of a funnel-web spider, blocks the P/Q type (Cav2.1), while omega-conotoxin from a cone snail blocks the N type (Cav2.2). Many synapses in the brain use both variants alongside each other, each in its own ratio. A third type, Cav2.3 or the R type, accounts for a smaller share at some terminals.
What Keeps a Channel in Its Place
The channels are not scattered at random. Scaffold proteins such as RIM and RIM-binding protein pin them down, a few dozen nanometers away from the sites where vesicles dock. In lab animals lacking RIM, the channels drift farther off and release grows less dependable.
Sensor and Fusion Machinery
Calcium contributes to normal neurotransmission.
EU-authorized wording · Regulation (EU) No 432/2012Two C2 Domains, Five Binding Sites
Synaptotagmin-1 spans the vesicle membrane with one short segment, while the larger part juts out into the cytoplasm. Out there sit two folded modules, C2A and C2B. When calcium binds, loops of these modules dip into the lipid layer of the cell membrane and bend it slightly. Mouse studies from the lab of Thomas Sudhof showed in 1994 that without synaptotagmin-1, fast synchronous release largely fails to happen, whereas a slower, scattered release is still present.
Synaptobrevin, Syntaxin-1 and SNAP-25
Together these three proteins make up the SNARE complex. Their long helices coil into one another from the vesicle side and the cell membrane side, a little like a zipper closing. Complexin holds the half-closed state in place, and Munc18 and Munc13 line up the partners beforehand. How much hinges on this bundle could be read from bacterial toxins: tetanus and botulinum toxins cut individual SNARE proteins and so interrupt release.
Calcium contributes to normal neurotransmission. EU-authorized wording · Regulation (EU) No 432/2012. The claim describes a normal body function that calcium takes part in. It says nothing about a larger intake altering that function, and it does not refer to any disease.
Counting Nanometers: Micro- and Nanodomains
Because proteins in the cytoplasm capture calcium at once and carry it away, a raised level stays confined to a tiny cloud around the pore. In 1992, Rodolfo Llinás, Mutsuyuki Sugimori and Robert Silver made such zones visible at the squid synapse with a light-emitting protein and named them microdomains.
Two Calcium Traps Compared
Two synthetic binding molecules offer a neat clue to the distance. EGTA grabs calcium slowly, BAPTA very fast. In 1991, Elis Adler, George Augustine and colleagues injected both into the squid terminal, and only BAPTA held release back to a marked degree. So the sensor has to sit close enough to the pore that a slow trap arrives too late – by current estimates, somewhere between 10 and 100 nanometers at many synapses.
| Preparation | Estimated distance | What the experiment hints at |
|---|---|---|
| Squid giant synapse | very tight | EGTA does little, BAPTA inhibits |
| Calyx of Held, young animal | fairly loose, up to beyond 50 nm | EGTA inhibits noticeably |
| Calyx of Held, mature animal | tighter than in the young animal | responds less to EGTA |
| Basket cells in the hippocampus | about 10–20 nm | nanodomain coupling |
A Timeline of Findings Since 1952
What is known about calcium at the synapse has built up in stages, often set off by a new preparation or a new way of measuring.
| Year | Finding | Research team |
|---|---|---|
| 1952 | spontaneous miniature potentials at the end plate, read as packets of messenger substance | Fatt, Katz |
| 1967 | calcium acts only if it is present during depolarization | Katz, Miledi |
| 1967 | release rises roughly with the fourth power of the external calcium level | Dodge, Rahamimoff |
| 1970 | Nobel Prize for work on chemical signaling between cells | Katz, von Euler, Axelrod |
| 1990 | cloning of synaptotagmin | Perin, Sudhof and co-workers |
| 1993 | SNARE hypothesis of membrane fusion | Sollner, Rothman and co-workers |
| 2013 | Nobel Prize for vesicle traffic in cells | Rothman, Schekman, Sudhof |
Since the 2010s, crystal structures have given a picture of how synaptotagmin, complexin and the SNARE complex fit against one another. The basic question Katz and Miledi asked – exactly when the calcium has to be there – can now be traced down to individual amino acids.
Asked and Answered
Does the Calcium Level in Blood Serum Hinge on the Last Meal?
Barely. Hormones hold the ionized fraction within a narrow band, whether or not someone has just eaten. The body evens out whatever food delivers through uptake, excretion and its reserves.
Why Does the EU Claim Name Calcium but Not Sodium?
Health claims are reviewed and authorized nutrient by nutrient. For signaling between nerve cells, Regulation (EU) No 432/2012 contains the calcium wording; other ions either appear there with claims of their own, phrased differently, or are absent altogether.
Can the Chronicle Stand In for a Neurophysiology Textbook?
That is not what it sets out to do. It picks out one single process and explains it in plain language. Readers who want to dig further will find the original papers each section draws on listed inside.
In What Form Does the Chronicle Arrive?
As a PDF file. After your payment comes in, you get a link by email that lets you download the file and read it on as many of your own devices as you like.