Cell Signaling Lectures and slides with some extra things mentioned in class!

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16 Oct 2011
Cell Signaling
Lecture 1: General Principles of Receptor Signaling
- Major obstacle to the development of multicellular organisms was the development of a means for individual
cells and tissues to communicate with each other and their environment.
- Purpose of cell signaling (communication) is to permit the development of complex mechanisms to govern
behaviour of cells for the overall benefit of the organism; single receptor on single cell can cause complex
mechanism behavioural variations.
Cell Signaling Contributes to:
- The regulation of metabolic processes
- Cell growth and differentiation
- The integration of normal physiological responses
Combination of signals evokes
different responses (diagram on the
Ach has completely different effects
on different cells and receptors
(diagrams on the right).
All living things are made of cells (individual units of living matter)
that share the same machinery for their most basic functions
Molecules (Ion, protein, drug) Molecular Machine (Receptor) Cell
Tissue Organ System Person
Components of Cell Signaling
1. Extracellular Signaling Molecules (ligands, first messengers): produced by the cell to signal neighboring
cells and/or to regulate their own function. Either released by a cell (actively and passively) or expressed on
the cell surface.
2. Receptor Proteins: bind an extracellular ligand and transduce the information provided by the signaling
molecule to the inside of the cell.
3. Intracellular Signaling Molecules (second messengers) and Signaling Proteins: distribute signal to
appropriate parts of the cell. Intracellular signaling proteins include proteins that are protein kinases, GTP-
binding proteins, adaptors and phosphatases.
4. Target Proteins: activities are altered when signaling pathway is active and changes behavior or activity of
the cell.
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An Organized Series of Cellular Responses (diagram on the left).
Signaling Molecules
- Proteins, small peptides, amino acids, nucleotides, steroid,
retinoids, hormones, lipids, growth factors, fatty acid
derivatives, ion, pheromones, light and dissolved gases such
as NO and CO2.
Signaling Molecules are:
i) Secreted from the signaling cell into the extracellular space
by exocytosis.
ii) Released by passive diffusion through the plasma
membrane (lipophylic).
iii) Exposed to the extracellular space but remain tightly bound
to the surface of the signaling cell.
Target cell, regardless of signal, responds by specific receptor protein. Binding of the signaling molecule (first
messenger) is the primary event, which initiates a response in the target cell. Receptor properties:
- Specificity – One receptor binds to one ligand at a time.
- Saturability – Ligand binding limited by number of receptors expressed on a cell. Maximum response is
related to number of receptors expressed.
- High-affinity – Many ligands act at very low concentrations <10-8M. Endocrine receptors tend to have high
affinity, whereas synaptic receptors may be lower affinity <10-6M, but are still highly specific.
The way in which each cell responds to its environment varies:
i) Receptor Expression/Complement: Set of receptors expressed by cell will determine its response.
ii) Intracellular Machinery: Depending on the intracellular machinery available to integrate and interpret the
info the cell receives e.g. the complement of kinases, ion channels, phosphatases, etc.
iii) Ligand Targets/Receptor Specificity: A single ligand can produce different physiological effects on
different target cells by binding to multiple receptors that are coupled to distinct effector pathways or by
binding to distinct receptor subtypes (ex. Ach) – differential expression of target proteins.
Acetylcholine – refer to previous diagrams a) and c).
1. Decrease rate and force of contraction of heart muscle, mAChR
(G coupled).
2. Stimulates skeletal muscle contraction, nAChR (ion channel). –
Note: Different receptors and 2nd messengers.
Classes of Receptors
1. Intracellular Receptors
- Cytosolic/nuclear (steroid receptors) bind to hydrophobic
- Many diverse ligands but have similar mechanism of action
leading to the activation and direct regulation of transcription of specific genes.
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2. Cell Surface Membrane Receptors
- Large number of different receptors divided into distinct
receptor “superfamilies”.
- E.g. G-Protein-Coupled Receptors, enzyme linked receptors,
ligand gated ion channel receptors.
- Majority of receptors are expressed at surface of a target cell
and are activated upon ligand binding. Ligands for these
receptors are hydrophilic and unable to pass the plasma
membrane or are too large.
Subclasses of Cell Surface Receptors (based upon
transduction mechanisms used).
- Ion Channel-linked Receptors (transmitter-
gated ion channels)
- Ligand transiently opens or closes the ion
channel formed by the protein to which it
binds leading to brief changes in ion
permeability across the plasma membrane
and excitability of the target cell.
- These are multi-pass 4-5 transmembrane spanning proteins that are comprised of multiple subunits that
exhibit different properties based on subunit composition (cell specific subunit expression). e.g. nAChR,
- G-Protein Linked Receptors
- Indirectly regulate activity of other
plasma membrane-bound target
proteins (either enzymes or ion
- Interaction between receptor and
target protein is mediated by
intermediary protein, the G protein
(trimeric GTP-binding regulatory
- Binding of ligand to receptor leads to activation and alteration in concentration of one or more intracellular
mediators, or ion permeability at plasma membrane.
- Agonist activation leads to changes in effector enzyme activity through receptor-regulated changes in the
function of intermediary G proteins.
- 7 transmembrane spanning proteins that comprise the largest superfamily of receptor proteins.
- Enzyme-Linked Receptors
- Binding of ligand to receptors leads to
direct activation of receptor-linked
enzyme, or indirect activation of
associated enzymes.
- Most are heterogenous single-pass
transmembrane proteins that form
receptor dimers with ligand-binding sites
localized to the extracellular domain and
catalytic sites localized to the intracellular
domain of the receptor.
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