Muscle activity involves biochemical reactions that produce heat due to ________ being converted to ____________
ATP
ADP
Apart from conversion of ATP to ADP, heat is also generated by what?
Movement of muscle contractile proteins
What are the main extracellular signalling groups?
Endocrine
Paracrine
Autocrine
Endocrine signalling involves which class of molecule?
Hormones
What are the major types of endocrine signalling molecules/hormones?
Hydrophilic 1 - Amines (Chatecholamines) e.g. Noradrenaline
Hydrophilic 2 - Peptides to proteins e.g. Insulin
Lipophilic- Steroids e.g. Testosterone
What are the time courses of action of amines, proteins and steroids?
Amines: milliseconds - seconds
Proteins: minutes- hours
Steroids: hours- days
Where are the receptors for each of these type of extracellular signalling molecule?
Amines
Proteins
Steroids
Amines- within the plasma membrane
Proteins- within the plasma membrane
Steroids- Intracellularly, within the cytosol or nucleus
What is the plasma half life of:
1) Chatecholamines
2) Peptides to proteins
3) Steroids
1) Seconds
2) Minutes
3) Hours
What do exogenous analogous signalling molecules do?
They attempt to mimic endogenous signalling molecules
Give two examples of exogenous endocrine analogues and what they might be used for.
Adrenaline- administered IV in emergency situations
Insulin- allows adequate control of blood sugar in diabetic patients
What is paracrine signalling?
Signalling from one cell which induces change in nearby cells
Are paracrine signalling molecules are released intra- or extracellularly?
Extracellularly
Signalling molecules that signal from neurone to neurone are known as what?
Neurotransmitters
Multiple synapsing of the CNS allows what?
Parallel processing of information
Transmission velocity of neurotransmitters is measured in what?
Milliseconds
What common neurotransmitter is excitatory at the end organ?
Acetylcholine (ACh)
Give 4 examples of monoamine neurotransmitters? State whether they are stimulatory or inhibitory.
Adrenaline - stimulatory
Noradrenaline - stimulatory
Dopamine - stimulatory and inhibitory
Serotonin
Give three examples of amino acids that act as neurotransmitters? State whether they are excitatory or inhibitory.
Glutamate- Excitatory
Glycine- Mostly inhibitory
GABA- Inhibitory
Local chemical meditators can also be examples of _________ signalling molecules
Paracrine
Some local chemical mediators can be classified as ____________ and ___________
Cytokines
Eicosanoids
Give four examples of cytokines
Interleukins
Chemokines
Interferons
Histamine
Give two examples of Eicosanoids
Prostaglandins
Leukotrienes
Besides Cytokines and Eicosanoids name four other local chemical mediators
Bradykinin
Nitric Oxide
Neuropeptides
Platelet Activating Factor
When would local chemical mediators be released?
Following local injury
What are the advantages of eliciting a local response?
It is rapid, focused and integrated and does not need to involve the whole body resource
Give three examples of the therapeutic application of paracrine signalling molecules of the neurotransmitter variety
Dopamine precursors and agents- inhibit dopamine breakdown in Parkinsonism
Fluoxetine- SSRIs to slow the reuptake of Serotonin in the CNA in depression
GABA receptor modulators/reducers of GABA synthesis- In epilepsy
Therapeutic paracrine signalling molecules that act as local chemical mediators can be used to treat what?
Inflammation (Steroids)
Moderate pain (NSAIDs)
Respiratory Inflammation
What is autocrine signalling?
When cells respond to signalling molecules that they produce and release themselves
Autocrine signalling shares many signalling molecules what what other signalling type? Such as?
Paracrine signalling
Such as cytokines and growth factors
Autocrine signalling molecules typically act over what distances when released from the cell?
Microns (Micrometres)
Endogenous and exogenous signalling molecules bring about a __________ in functional status
Change
The signal produced when a signalling molecule binds its target can function to _______ the original signal to produce another signal, and ultimately perform a specific task e.g. _______ or ________
Transform
Transport
Synthesis
Endogenous signalling molecules have been engineered by ____________ and therefore carry out their function optimally
Evolution
Exogenous signalling molecules are often engineered by _________ _________ to carry and transfer their ‘imposter’ signal. The signal is still carried, but the _____ may be sub-optimal.
Human design
Fit
Exogenous signalling molecules may produce unwanted _____________.
Side effects
Name 4 classes of targets for signalling molecules
Receptors
Ion channels
Transporters
Enzymes
Name the 4 types of RECEPTORS that signalling molecules may act on
Kinase-linked receptors
Ion channels (Ligand Gated!!)
Nuclear/intracellular
G Protein Couple Receptors (GPCRs)
Name the three types of ion channels
Ligand gated
Voltage gated
GPCR modulated
Kinase-linked receptors have a timescale of what?
Hours
Kinase-linked receptors bind ligands such as?
Growth factors
Cytokines
Hormones
How do kinase-linked receptors work?
Via phosphorylation of specific groups which activates a SIGNALLING CASCADE leading to gene transcription e.g. growth/differentiation
Ligand gated ion channels are a type of receptor. What are these receptors also known as? What does this mean?
Ionotropic receptors
They form an ion channel pore
What is the time scale of ligand gated ion channels?
Milliseconds
Ligand gated ion channels gate the flow of _____ across the plasma membrane for the duration of ________
Ions
Binding
Give some examples of ligands that may bind to a ligand-gated ion channel
Neurotransmitters such as: Acetyl Choline (ACh), GABA and NMDA
Ligand gated ion channels allow _____ currents and _________ change which can drive or modulate action potential generation in ________ and ________ in muscle
ion
voltage
neurones
contraction
Nuclear/ Intracellular receptors have a time scale of what?
Hours
In order to bind to a nuclear/ intracellular receptor, ligands need to be what?
Lipid soluble
Once the ligand is bound, what happens at the nuclear receptor?
The ligand-receptor complex migrates to the nucleus, if it is not already there, and binds to a TRANSCRIPTION FACTOR
Once the ligand-receptor complex is bound to a transcription factor, what happens?
A set of genes are activated or inactivated
Apart from steroids, what other ligands can bind to nuclear/intracellular receptors?
Thyroid hormone, Vitamin D, Xenobiotics
GPCRs are also known as what type of receptor?
What does this mean?
Metabotropic receptors
It is a membrane receptor that acts through secondary messengers
What are the largest family of receptors?
GPCRs
Give two examples of groups of molecules that can bind to GPCRs
Hormones
Opiates
What is the time scale of GPCRs?
Seconds
Give two examples of GPCRs that have ligands that are neurotransmitters
Musclarinic acetyl choline (ACh) receptor (serotonin) and adrenoceptors (dopamine)
What are the three major types of GPCR?
Gq, Gi and Gs
What is the difference between ionotropic and metabotropic receptors
Ionotropic: form an ion channel pore in the cell membrane
Metabotropic: acts by signal transduction through a secondary messenger
Ion channels are another target of cell signalling molecule. How do they work?
By selectively allowing ion current to flow across the plasma membrane
Name 4 major ion currents
Na+ (Sodium ions)
K+ (Potassium ions)
Ca2+ (Calcium ions)
Cl- (Chloride ions)
Ion channels regulate voltage signals in excitable cells to maintain _________________
Membrane potential
True of false: Ion channels are selective
True
Voltage- gated ion channels (VGICs) primary activity is dependent on change in ______ ______ density
electric field
Ion channel activity can be facilitated or inhibited by ___________ of intracellular sits on channels via GPCR Protein Kinase A and Protein Kinase C activation
Phosphorylation
Activity of ion channels can be allosterically modulated by endogenous intracellular signalling molecules such as ______, _______ and Ca2+ signalling proteins e.g. _____________
ATP
GTP
e.g. Calmodulin
Transporters/Carriers in the plasma membrane do what via which methods of movement?
Transport ions or small molecules using FACILITATED DIFFUSION or ACTIVE TRANSPORT
With regard to movement of molecules, what features will determine whether movement is achieved by facilitated diffusion or active transport?
The concentration gradient (against a gradient=active transport)
The size of the molecule (large= active transport)
The polarity of the molecule (polar molecules= active transport)
What energy sources are required to achieve active transport?
ATP or a pre-existing ion gradient (in symport/antiport)
Which transporters are responsible for the efflux of drugs and imposter molecules from cells?
Multi-drug Resistance Proteins (MDRPs)
Part of the ATP-binding cassette ABC superfamily
An important example of transport in the body is in neurotransmitter re-uptake. Give three examples of neurotransmitters that would be taken back up in this way.
Serotonin
Glutamate
Noradrenaline
Co-transport of _____ can be used to drive transport. This type of transport is known as _________.
Na+ (Sodium ions)
Symport
List 3 common uses of enzymes
Signal processing
Degradation
Synthesis
Give an example of competitive inhibition at active binding site by a drug.
Aspirin binding to COX enzyme
