2. Background
• Cells depend on signalling systems to adapt to changing
environmental conditions.
• Free-living organisms, respond to changes in temperature, osmotic
stress, and nutrients by synthesizing the proteins required to their
survival
• Motile cells respond to chemicals by migrating toward attractants and
away from repellents
• Main molecular components of signalling pathways: receptors,
protein messengers, and second messengers
3.
4. Receptors vs Stimuli
• Cells use molecular receptors to detect chemical and physical stimuli.
• Physical interaction of the stimulus with the receptor provides energy
to modify the structure of the receptor and initiate a signalling
pathway
• With the exception of RNA “riboswitches,” all receptors are proteins
• A few stimuli, including light, steroid hormones, and gases, penetrate
the plasma membrane and react with receptors inside the cell
5. Receptors vs Stimuli
• Active receptors generate a chemical signal inside the cell by
interacting with one or more cytoplasmic proteins
• This transduction step converts one type of signal (the stimulus) into
another signal (the messenger) and often amplifies the signal
• GTP binding activates these G-proteins, allowing them to bind and
regulate target proteins.
6.
7. Second Messengers
• These second messengers are chemically diverse, ranging from
hydrophobic lipids confined to membrane bilayers, to an inorganic ion
(Ca2+ ), to nucleotides ( [cAMP] and [cGMP]), to a gas (nitric oxide)
• They modify cellular behaviour by binding to and activating a wide
range of effector proteins, regulating membrane physiology, cellular
metabolism, motility, and gene expression.
• Effector systems include transcription factors
8.
9.
10. Calcium Signalling
• Calcium ion, Ca2+ , is a versatile second messenger that regulates many
processes, including synaptic transmission, fertilization, secretion, muscle
contraction, and cytokinesis.
• Ca2+ is released into and removed from the cytoplasm
• ATP-driven Ca2+ pumps in the plasma membrane and ER keep cytoplasmic
Ca2+ levels low
• A variety of stimuli, operating through different receptors open Ca2+
channels, allowing a concentrated burst of Ca2+ to enter the cytoplasm
13. Biochemical approach
• Identification of a naturally occurring or synthetic chemical, that
modify the activity of an organism, organ, or cell
• These compounds are called agonists, effects of agonists are often
aided by the discovery of antagonists
• Antagonists prove to be useful as drugs
These extracellular ligands bind transmembrane receptors on the cell surface that transfer the signal across the lipid bilayer
Most stimuli act through one of approximately 25 families of receptor proteins, each coupled to a distinct signal transduction pathway
For example, of 20,447 genes in the nematode genome, nearly 800 encode a large family of receptors with seven transmembrane helices
The cytoplasmic domains of active seven-helix receptors catalyze the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP) on signal-transducing guanosine triphosphatases (GTPases), called G-proteins. GTP binding activates these G-proteins, allowing them to bind and regulate target proteins.
Some receptors have a cytoplasmic domain with protein kinase activity or associate with a separate protein kinase.
These enzymes transfer phosphate from adenosine triphosphate (ATP) to specific amino acids on target proteins.
Understanding signaling pathways can be challenging. First, cells employ hundreds of distinct signaling pathways, involving hundreds to thousands of different proteins. Second, few signal transduction mechanisms involve simple linear pathways from a stimulus to a change in behavior. Rather, most pathways branch and converge multiple times. Thus information from several inputs can influence each effector system. This provides for integration of regulatory mechanisms but makes it difficult to predict how information flows through a system. Third, most pathways have positive or negative feedback loops that can either augment or inhibit responses. Fourth, the response of some pathways depends on both the strength and the temporal pattern of the stimulus. Ultimately, signaling pathways must be understood as integrated systems, like complex electrical circuits.
Rather than being synthesized and metabolized like all other second messengers,
Calcium-Release Channels Voltage-gated and agonist-gated channels in the plasma membrane (Table 26.3 and Fig. 26.12) admit Ca2+ into the cytoplasm from outside. Chapter 16 explains how the membrane potential or agonists open these channels. Voltage-gated channels are essential for rapid responses in excitable cells such as muscles and neurons. Owing to rapid inactivation by negative feedback from the released Ca2+ , most of these channels produce brief, self-limited Ca2+ pulses. Two types of agonist-gated channels—called IP3 receptors and ryanodine receptors—release Ca2+ from the ER. Striated muscles uses ryanodine receptors, whereas smooth muscle and nonmuscle cells have both types of release channels (Table 26.2). In excitable muscle cells, plasma membrane Ca2+ channels trigger ryanodine-receptor channels to release Ca2+ from the ER. In nonexcitable cells, stimulation of either seven-helix receptors or receptor tyrosine kinases produces IP3, which triggers IP3 receptors to release Ca2+ from the ER.
