Cell Signaling 1

This lecture is an introduction to a series of lectures on cell signaling. The first lecture is a general introduction to the different signaling mechanisms and second messengers. The lecture will also describe the signaling pathways through cytoplasmic and nuclear steroid signaling pathway. The following lecture (2) looks in detail at some specific examples of signaling pathways through membrane receptors.

Note that you have already been introduced to signaling in many of your other lecture topics.

Lecture Slides: 2017 Lecture PDF | 2017 Lecture PDF 4 slides/page

Note - The information shown on this page below is for background purposes only, the slides linked above will be used in this lecture presentation.

Archive: 2016 | 2015 | 2013 | 2010 lecture | 2009 lecture

Movie - Neutrophil chasing Bacterium

Objectives

Understand main types of signaling mechanisms
Understand concept of receptor and ligand
Understand membrane, cytoplasmic and nuclear receptors
Brief understanding of steroid hormone pathway
Brief understanding protein growth factor pathway
Understand differences between select membrane receptors (G protein structure, tyrosine kinases)

Lecture Summary

Messengers and Receptors
chemical signals
cellular receptors
signal transduction
intracellular pathways
second messengers
Examples of signaling

Signaling Mechanisms

MCB - Extracellular Signaling

Endocrine - Hormone (at a distance)
Paracrine - Locally
- Neurotransmitter - Specific form of paracrine
Autocrine - Local (self)
- Contact Dependent

Cell Communication

Contact Mediated - display molecules on cell surface, recognized by receptor on another cell
Non-Contact Mediated - chemical signal, nearby or at a distance
Common Signals Signals and Receptors

Chemical Signal Types

water soluble
lipid soluble

Movie: Hormone Signaling

Extracellular Signal Steps

Signaling Molecule

Synthesis
Release by signaling cell
Transport to target cell
Detection by a specific receptor protein
Change by receptor-signal complex (trigger)

There can also be a feedback mechanism following signaling.

Cell Surface Receptors

four main classes
- G protein–coupled receptors
- ion-channel receptors
- receptors linked to cytosolic tyrosine kinases
- receptors with intrinsic catalytic activity
ligand binding to cell-surface receptor
- trigger intracellular pathways
- modulate cellular metabolism, function, or development
Removal of the signal
- often terminates cellular response

Second Messengers

Cyclic adenosine monophosphate (cAMP)

Cyclic guanosine monophosphate (cGMP)

Cyclic nucleotides - cAMP, cGMP (will cover also in next lecture G protein signalling)
Calcium Ions
Inositol 1,4,5-trisphosphate (IP3) (see also IP3 receptor PMID 9243320) IP3 receptor plays in the conversion of numerous external stimuli to intracellular Ca2+ signal
Diacylglycerol (DAG) - modified lipid activates PKC
Protein Kinase A - PKA, B, C (phosphorylate other proteins)
regulate the activity of cellular proteins (enzymes and non-enzymatic)

Links: Cell - Common intracellular signaling proteins Elevation of cytosolic Ca2+ via the inositol-lipid signaling pathway | Movie: Second Messengers in Signaling Pathways

Steroid Responses

Steroid hormone receptor signaling

Steroidogenesis

Intracellular Receptors (longest acting of hormone classes, hours-days)
Steroid Hormones (androgens, glucocorticoids, mineralocorticoids)
- MCB - Steroid Hormones, Thyroxine, and Retinoic Acid | Cell - Structure of steroid hormones, thyroid hormone, vitamin D 3, and retinoic acid
- thyroxine (thyroid, not a steroid)
- vitamin D3
- retinoic acid
- cortisol (adrenal)
- estrogens and testosterone (gonad)
All steroid hormones are synthesized from cholesterol.
Steroid hormones are less soluble in aqueous solution, most in blood as complexes bound to specific plasma globulins or albumin (synthesised in the liver)

Steroid_signaling_cartoon

Other Endocrine Axes

Hypothalamus - Pituitary - Adrenal
Hypothalamus - Pituitary - Thyroid
Hypothalamus - Pituitary - Gonad (female)
Hypothalamus - Pituitary - Gonad (male)

MCB - Characteristic Properties of Principal Types of Mammalian Hormones | MCoB - Some signaling molecules that bind to nuclear receptors | Cell - Action of steroid hormones

Steroid Hormone Receptors (SHRs)

Steroid hormone receptor signaling

Cytosol location

receptor bound to inhibitor
ligand binding activates receptor
translocates to nucleus on ligand binding

Nuclear location

binds ligand and DNA
becomes transcription factor

estrogen receptor, two forms ERα [NR3A1] and ERβ [NR3A2]
cortisol binding glucocorticoid receptor (GR) [NR3C1]
aldosterone binding mineralocorticoid receptor (MR) [NR3C2]
progesterone receptor (PR) [NR3C3]
dihydrotestosterone (DHT) binding androgen receptor (AR) [NR3C4]

Steroid_signaling_cartoon

Nuclear Receptor Signaling

Receptor Structure

Nuclear Receptor

steroid binding region - near C-terminus
DNA binding - central region
- zinc finger motif
- alpha helix and 2 beta sheets held in place by cysteine or histidine residues by a zinc atom
- multiple fingers typical
DNA response element
Enhancer

Links: Box 1.12Steroid receptors, zinc fingers and DNA binding

Receptor Types

48 human nuclear receptor types

Steroid hormone receptor family

Type I Receptors
- Sex hormone receptors (sex hormones) - Androgen receptor, Estrogen receptor, Progesterone receptor
- Glucocorticoid receptor (glucocorticoids)
- Mineralocorticoid receptor (mineralocorticoids)
Type II Receptors
- Vitamin A receptor
- Vitamin D receptor
- Retinoid receptor
- Thyroid hormone receptor
Orphan receptors

Links: nuclear-receptor superfamily three classes | Image - Models of sex steroid action in target tissue

Eicosanoids

(icosanoids) prostaglandins, prostacyclins, thromboxanes and leukotrienes
lipids acting as signaling molecules
- made from essential fatty acids (EFAs) oxidation (arachidonic acid)
act by binding to cell surface receptors, rapidly broken down (anti-inflammatory drugs act by downregulating eicosanoid synthesis)
act locally in autocrine or paracrine signaling pathways

Links: Eicosanoid biosynthesis cartoon | Prostaglandins

Nitric Oxide

(nitrogen monoxide) another signaling method that crosses lipid membranes
simple gas, very quick short-lived signal
- synthesised from arginine by nitric oxide synthase
does not bind intracellular receptor
- regulates intracellular enzymes

Example - dilation of blood vessels. (nitroglycerine for heart converted to NO)

References

Textbooks

Essential Cell Biology

Essential Cell Biology Chapter 15

Molecular Biology of the Cell

Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter New York and London: Garland Science; c2002

Molecular Biology of the Cell 4th ed. - IV. Internal Organization of the Cell Chapter 15. Cell Communication
Cell Communication
General Principles of Cell Communication
Figure 15-12. Some signaling molecules that bind to nuclear receptors

Molecular Cell Biology

Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. New York: W. H. Freeman & Co.; c1999

Molecular Cell Biology - Chapter 20. Cell-to-Cell Signaling: Hormones and Receptors
Cell-to-Cell Signaling: Hormones and Receptors
Overview of Extracellular Signaling
Steroid Hormones, Thyroxine, and Retinoic Acid
Table 20-1. Characteristic Properties of Principal Types of Mammalian Hormones
Figure 20-6. Schematic overview of common signaling pathways downstream from G protein–coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs)

The Cell- A Molecular Approach

Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000

The Cell - A Molecular Approach - IV. Cell Regulation Chapter 13. Cell Signaling
Cell Signaling
Modes of Cell-Cell Signaling
Figure 13.2. Structure of steroid hormones, thyroid hormone, vitamin D 3, and retinoic acid
Figure 13.3. Action of steroid hormones

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"cell signaling" Molecular Biology of the Cell | Molecular Cell Biology | The Cell- A molecular Approach | Bookshelf

"steroid signaling" Molecular Biology of the Cell | Molecular Cell Biology | The Cell- A molecular Approach | Bookshelf

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Reviews

Articles

External Links

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2017 Course Content

Moodle

2017 Laboratories: Introduction to Lab | Fixation and Staining |

2017 Projects: Group 1 - Delta | Group 2 - Duct | Group 3 - Beta | Group 4 - Alpha

Dr Mark Hill 2015, UNSW Cell Biology - UNSW CRICOS Provider Code No. 00098G

Signal 1

Contents