To make a multicellular organism, cells must
be able to communicate with one another, and to do it cells often send out tiny chemical
signals that act on the receptors on other cells. Signals can be classified according to the
distance between the signaling cell and the target cell. Autocrine signals are produced by a cell and
go to its own receptors, so the cell sends a signal to itself. Paracrine signals are produced by a cell and
go to target cells that are nearby. And endocrine signals are produced by a cell
and go to target cells that are further away. Examples of these include hormones that are
secreted into the bloodstream, as well as cytokines that can be released at the site
of injury and act on the brain to cause a fever. Signaling molecules or ligands can be hydrophobic,
meaning that they tend to repel water, or hydrophilic, meaning that they tend to stay
in water. Hydrophobic signalling molecules can’t freely
float in the extracellular space, so they’re brought to the target cells by carrier proteins. Hydrophobic molecules can diffuse across the
cell membrane and bind to receptor proteins inside the target cell - either in the cytoplasm
or in the nucleus. Most signal molecules are hydrophilic, so
they can freely float in the extracellular space to reach the target cells, but are then
unable to cross the cell membrane. So to pass on the signal, hydrophilic molecules
bind to receptors on the cell surface. These receptors are transmembrane proteins,
with an extracellular end that binds to the ligand, and an intracellular end that triggers
a signaling pathway inside the cell. We can think of the cell signaling pathway
in three stages. The first stage is reception, which is when
the target cell’s receptor binds to a ligand. It’s like a key fitting into a lock. Then there’s transduction, which means that
the receptor protein changes in some way and that activates intracellular molecules - the
second messengers. The third stage is the cell’s response to
the signal. Zooming into these transmembrane receptors,
there are three major classes: G protein coupled receptors, enzyme-coupled receptors, and ion
channel receptors. G-protein coupled receptors are seven pass
transmembrane receptors. These are really long proteins that have one
end that sits outside the cell and binds the ligand, then the snake-like protein dips in
and out of the cell membrane seven times, and finally ends on the inside of the cell. The end of the G-protein coupled receptor
that’s within the cell activates intracellular proteins called guanine nucleotide-binding
proteins or G proteins. G proteins are made up of three subunits called
alpha, beta, and gamma, sort of like a flower with three petals. The alpha and the gamma subunits are anchored
to the cell membrane and keep the G protein right next to the receptor. G proteins bind to guanosine diphosphate or
GDP when they’re inactive. When the alpha subunit is bound to GDP, the
three subunits stay together, so the flower is closed. But when the ligand binds, the G-protein coupled
receptor changes its shape, and this allows the G protein to release GDP and bind GTP
instead, activating the protein. When the alpha subunit is bound to GTP, the
alpha subunit separates from the beta and gamma subunits, like one petal opening and
separating from the others. When that happens, the alpha subunit is free
to interact with other proteins - it stimulates some while inhibiting others. But, to act on other proteins, the alpha subunit
turns GTP into GDP, and when that happens the three subunits come together again - the
flower closes - and the G protein is turned off. Overall, there are three types of G proteins:
Gq, Gi, and Gs, and each one stimulates and inhibits a different set of enzymes and molecular
pathways. The Gq protein activates the enzyme phospholipase
C, which is found in the cell membrane. Phospholipase C then cleaves a phospholipid
called phosphatidylinositol 4,5-bisphosphate into inositol trisphosphate and diacylglycerol. Inositol trisphosphate is soluble and diffuses
freely through the cytoplasm and into the endoplasmic reticulum where it opens up calcium
channels. Since the calcium concentration is higher
in the endoplasmic reticulum than in the cytoplasm, calcium flows out of the endoplasmic reticulum
to the cytoplasm. The increased calcium concentration in the
cytoplasm changes the electrical charge of the cell and can lead to depolarization. Meanwhile, diacylglycerol remains attached
to the cell membrane and binds to the enzyme protein kinase C, which also relies on calcium
to fully activate. Once calcium levels in the cell go up, protein
kinase C starts to activate proteins by adding phosphoryl groups to them. Next is protein Gs which stimulates the enzyme
adenylate cyclase. Activated adenylate cyclase takes adenosine
triphosphate or ATP, and removes two phosphate molecules transforming it into cyclic adenosine
monophosphate or cAMP. cAMP moves throughout the cytoplasm and binds to the enzyme protein
kinase A. Protein kinase A has two parts - a regulatory subunit and a catalytic subunit,
and cAMP specifically binds the regulatory subunit of protein kinase A. When cAMP binds
it makes the regulatory subunit dissociate from the catalytic subunit of protein kinase
A. It’s like pulling the pin out of the fire extinguisher allowing it, in this case
the catalytic subunit, to do its job. So after dissociating, the catalytic subunit
of protein kinase A is free to phosphorylate target proteins that trigger a cellular response. Finally, there’s the protein Gi, which is
also bound to adenylate cyclase - but in this case, inhibits it, causing negative feedback
on protein Gs. This is particularly important in helping
to inactivate cells. Next are the enzyme-coupled receptors. They’re usually single-pass transmembrane
proteins, meaning that they have only one transmembrane segment, and their intracellular
end has intrinsic enzyme activity. In other words, enzyme-coupled receptors have
two parts - one domain is the receptor and the other domain is an enzyme. Each domain has a separate function, like
a swiss army knife composed of both a knife and scissors. The enzymatic domain is usually a protein
kinase that phosphorylates the receptor domain. Now, there are three main types of enzyme-coupled
receptors, based on the amino acid the receptors get phosphorylated at. The first group are the receptor tyrosine
kinases. These are the most common enzyme-coupled receptors,
and there are many subfamilies. Receptor tyrosine kinase are generally molecules
that can’t phosphorylate their own tyrosine side chains. When a ligand binds, two receptor chains come
together and dimerize, and they cross-phosphorylate one another at multiple tyrosine residues. This triggers a conformational change that
creates high-affinity binding sites for the second messengers, which can also be phosphorylated
and activated, triggering the signaling pathway. Next, are the tyrosine kinase associated receptors
which work in nearly the same way as receptor tyrosine kinases, and their name even sounds
almost the same. The key difference is that they have no intrinsic
enzyme activity. Instead they’re associated with cytoplasmic
tyrosine kinases. When the receptors bind their ligand, the
cytoplasmic tyrosine kinases phosphorylate various target proteins to relay the signal. Finally, there are the receptor serine/threonine
kinases and they have a serine/threonine kinase domain on their intracellular end. There are two classes of these receptor serine/threonine
kinases - type I and type II - which are structurally similar. Ligand binding brings the two together together
so that the type II receptor can phosphorylate and activate the type I receptor, which in
turn recruits and phosphorylates various target proteins to relay the signal. Finally, there are the ion channel receptors
which are generally closed, but then open up once they bind a specific ligand. They allow ions like chloride, calcium, sodium,
and potassium to passively flow down their gradient. This leads to a shift in electric charge distribution
inside the cell, triggering a cellular response. Alright, as a quick recap, autocrine signals
target the same cell, paracrine signals target nearby cells, and endocrine signals target
distant cells. Hydrophobic ligands are able to diffuse across
the cell membrane and bind to receptor proteins inside the target cell. Hydrophilic ligands are unable to cross the
cell membrane, so they must bind to transmembrane receptors, which have an intracellular end
that triggers a signaling pathway inside the target cell. There are three major transmembrane receptor
classes: G protein coupled receptors, enzyme-coupled receptors, and ion channel receptors.
