These notes contain an introduction to the topic of cell signalling and more in detail description of some of the most important pathways in the cell and their receptors.
The notes include: different types of signalling, generic receptor description, hormone classification, insulin biosynthesis a...
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Test Bank For Lehninger Principles of Biochemistry, 7th Edition by LEHNINGER Chapter 1-28
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Cell Signalling
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CELL SIGNALLING
At any given time cells are communicating through millions of signals that can be either physical or
converted to chemical. In order to detect a chemical signal (hormones and neurotransmitters), the
target cell must have the correct receptor to receive that particular signal and trigger a response
(note that physical stimuli are converted to chemical at the level of the receptor). The signals are
often relayed inside the cell through a signalling pathway resulting in “change” (ex: metabolic
alteration, changes in gene expression, cellular process activation/deactivation) → extracellular
signal in converted into an intracellular response.
A first classification can be done on the basis of the distance of action of the ligand:
• AUTOCRINE SIGNALLING: the secreting cell is also the target (the cell stimulates itself);
the receptors for the released ligand are on the cell surface or inside that cell.
• CONTACT SIGNALLING: signalling molecules diffuse between neighbouring cells
directly via gap junctions (permeability regulated by [Ca2+], [H+], [cAMP], membrane
potential). This allows a cellular response to a signal that only one cell has received.
• PARACRINE SIGNALLING: cells communicate over a relatively short distance
(immediate surrounding area).
• ENDOCRINE SIGNALLING: signals can affect sites of the body that are much further
away; ligands (hormones) travel this distance via the blood stream, this means that they are
diluted during the way and reach their targets in low concentrations.
The response to a signal may occur in minutes (ex: changes in the activity of a protein) or take
hours/days (ex: metabolic or genetic alterations).
RECEPTORS
A receptor is composed of two domains: a ligand binding domain (LBG) and an effector domain
(ED). There can be multiple isoforms for both: two receptors might respond to the same ligand but
have different downstream effects (same LBD & different ED) or different ligands could have the
same overall effect (different LBD & same ED). One could also create a chimeric receptor with
novel properties (coupling different LBDs and EDs).
Because receptors act to accelerate an intracellular pathway they can be seen in many ways as
analogous to enzymes (some actually are), thus a series of properties can be identified:
1) SPECIFICITY: precise molecular complementarity between ligand and receptor (mediated by
weak, noncovalent interactions).
2) AFFINITY (between ligand and receptor): can be expressed as the dissociation constant Kd =
[R][L]/[RL], commonly ≤ 10-7 M (receptor detects micromolar to nanomolar concentrations of the
ligand).
3) SATURATION: concentration at which no more receptors are free to bind signal molecules.
, 4) COOPERATIVITY: receptor-ligand interaction results in large changes in receptor activation
with small changes in ligand concentration.
5) AMPLIFICATION: [RL] complex activates an enzyme that in turn catalyses the activation of
many molecules of another enzyme and so on, resulting in an amplification of the initial signal
within milliseconds (a cascade).
6) INTEGRATION: multiple signal (can have opposite/similar effects) combine to produce a
unified response.
7) DESENSITIZATION: when a signal in continuously present it causes the receptor to adapt and
no longer respond until the signal falls below a certain threshold.
The receptor-ligand interaction model suggests that receptors exist in one of two conformations: R
& R*, with the understanding that R* can exist even in the absence of an agonist. This means that R
may change conformation to R* even in the absence of the agonist A. A may bind to both states but
has a higher affinity for R*, thus stabilizing the active state and producing a cellular response.
(KA, inactive state)
A+R ↔ AR
(E0, vacant states) ↕ ↕ (E1, occupied states)
A + R* ↔ AR*
(KA*, active state)
Receptors can either be ionotropic (receptors are themselves ion channels) and metabotropic
(receptors that activate a second messenger).
The major classes of receptors are: gated ion channels (direct and rapid transmission), serpentine
receptor/G protein-coupled receptor (receptor activates an intracellular G protein which regulates
an enzyme that generates a second messenger), enzyme-linked receptors (either with intrinsic
enzyme activity or associated to and regulate one), steroid/nuclear receptor (receptor protein that
can regulate expression of specific genes, can be located in the cytosol or directly in the nucleus).
NICOTINIC ACETYLCHOLINE RECEPTOR (IONOTROPIC):
Pentameric structure (2 alpha subunits, 1 beta, 1 gamma, 1 delta), each subunit is composed of 4
transmembrane alpha-helices (M1 to M4). The binding sites for ACh are on the alpha subunits, and
the cations that pass through the channel are Na+, K+ and Ca++.
Hydrophobic leucine (on M2) residues are exposed to the pore when ACh is not bound, therefore
preventing cation passage. When ACh binds → allosteric modification generates rotation of M2 and
thus of leucine residues, exposing polar residues and allowing cation passage.
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