Neurotransmitter and receptors:Basics Flashcards
(30 cards)
What is meant by signal transduction?
The conversion on a external signal into a internal biological change
What is selective toxicity?
Essentially a stronger affinity for a specific binding site over other sites.
What is pharmacokinetics?
this is the study of drug movement. Looking at changes in drug concentration to locate sites of action and look at absorption and distribution.
What is Pharmacodynamics?
This looking at drug potency, I.e its affinity and efficacy for specific drug targets
3 ways of classifying drugs? (at least 2 examples for each)
By their therapeutic use: Pain killers, AED (Anti=epileptic drugs), Anti-dysrhythmias
By their mechanism of action: SSRIs (selective serotonin re-uptake inhibitors, Beta blockers, MAOIs (Mono-amine oxidase inhibitors)
Structure: Benzodiazepines, Caetecholamines
How to asses drug suitability for therapeutic use?
This is achieved by using the therapeutic index. originally Elrichs therapeutic index it was adapted to take into account the variability between patients. the minimum toxic dose in 50 patients is divided by the minimum effective dose. the larger the gap the safer the drug and the bigger the therapeutic index value.
Drug efficacy vs potency?
Drug efficacy is the maximum response a drug can cause.
Drug potency is the amount of drug required to cause a certain response.
3 main forms of LGICs?
LGICs can be pentameric (GABA A, 5-HT), Tetrameric (Glutamate), Trimeric (ATP)
Outline N.ACh as example of LGIC? (Structure+binding)
The nicotinic acetyl choline receptor i a pentameric example. usually having 2 alpha, a alpha-gamma, alpha-beta, and a alpha delta subunit.
The alpha sub units mark where the ACh binds, 2 need to bind to each at the point they associate with their neighbor for the channel to open.
Each sub unit has 4 trans-membrane regions.
What is the 3rd loop cytoplasmic of a GPCR associate with?
This loop is the point of association with the g-protein.
fatty chains on BY subunit allow for?
these allow for prenylation of the dimer anchoring it to the membrane.
Influence of Cholera and Pertusis on G-proteins?
Cholera toxin prolongs the activation of Gs alpha sub units by inhibiting the function of GTPase.
Pertusis toxin prevents the disscoaition of the alpha and beta-gamma dimer. this means that Go g-proteins are inhibited.
what is a Gt g-Protein?
Gt g-proteins activate GMP phosphodiesterase in vertebrate Rods.
What are RAMPs and RGSs?
Receptor Activity modifying Protein, these associate with G-proteins. They will alter there pharmacology and therefore the ligand binding the associated receptor will be associated with the RAMP, for example Calcitonin and RAMP1
Regulator G-protein signalling proteins, These bind the alpha sub-units and potentiate the activity of GTPases to limit the length of G-protein activity.
Outline the 3 types of kinase linked-receptors? (structure+example)
Receptor tyrosine kinases: this tend to be monomeric and have 1 trans membrane spanning region and a complex extracellular domain with a intra-cellular tyrosine selective kinase. These can be found in complexes like dimers in insulin.
Another example is the liposacharides recognition.
Threonine/serine kinases: these have a similar structure but are smaller an recognize serine and threonine residue instead. TGF is an exmaple of a ligand
Cytokine kinases: these have an intrinsic enzyme activity often associating with a intra-cellular cytosolic kinase like Janus kinase (Jak).
Ligands tend to be activated by cytokine like interferon.
Mech of RTK growth factor signaling (What other outcomes can they have)
The binding of the ligand, in this case GF, results in the dimerisation of the RTKS.
Upon dimerisation the intra-cellular tyrosine kinase domain autophosphorylate each-other, this activates them and increases there affinity for other intra-cellar proteins.
In this case it leads to the recruitment of GRB2 which is phorphoryalted (but essentially molecules with SH2 domains (affinity for tyrosine residues) are recruited).
GRB2 goes on to activate Ras by stimulating the swapping of a bound GDP fora GTP. this leads to the activation of RAF and the stimulation of the Map kinase phophotyaltion cascade.
This results in what is the aim of ll receptor linked kinases, and that the turning on or off of genes.
ALTERNATIVELY, phospholipase C could have been activated to form IP3 and leads to intracellular calcium release influencing cell division.
Briefly outline Nuclear receptors?
These are the slowest of the receptors and tend to react to steroid hormones and lipids
They’re essentialy transcription factors that are being by inhibitory complex to stop them influencing gene expression. the binding f the ligands counters this.
They are monomeric and have no membrane spanning domain.
What is the difference between Class 1 and 2 nuclear receptors (give examples)?
Class 1 proteins tend to lie in the cytosol and respond to lipid soluble steroid hormones that diffuse through the membrane and bind the receptors, Binding results in the translocation of the complex to the nucleus where it associates with the DNA to alter gene expression.
Examples is the reaction to Oestrogen and progesterone. This class tend to be associated to negative feedback loops.
Class 2: these act more like gate keepers making sure a molecule entering is safe and therefore can be seen alot to release antidiabetic and drug metabolizing enzymes in response to activation.
These tend to have lipid ligands that are already partially present in the cell. Receptor examples are live oxytosin receptor (LOR) and the peroxisome proliferator activated protein (PPaR).
another key thing to note is that these almost always exist as heterodimers with the retinoid receptor RXR. when in this configuration they can be permissive or non-permissive,this means they will react to the RXR ligand retinoic acid and its own ligand or retinoic acid alone, respectively.
outline the Sympathetic and para-sympathetic nervous systems pointing out similarities and differences?
The sympathetic nervous system is known for exciting the body whereas the para sympathetic nervous system is known for slowing and inhibiting the body. Both will target areas like smooth muscle and the heart.
The other key difference is their neurotransmitters. Although both use ACh at their pre-ganglionic synapses, at the post-ganglionic synapse the sympathetic nervous system secretes NA whilst the Para-sympathetic NS still secretes ACh although the pre and post-ganglionic receptors have a different pharmacology to one and other.
Sympathetic in spinal trunk Para in brainstem, upper spine and lower sacral spine.
The pre-ganglionic signalling is always a fast action signalling whilst the post-ganglionic signalling is always a slow-metabolic signalling.
the output from both is modulated by the nucleus solitary tract involving the limbic system and brain-stem nuclei in order to alter the autonomic outflow..
What is the heterotrophic nature of ACh and NA
There is a mutual ability to presynaptically inhibit the others secretion.
NA n ACH in the heart
ACh on NA in the myenteric plexus (part of the enteric NS)
Note that homo-tropic is what autoreceptors do.
Give examples of Co-transmission
These are other substances that are co-packaged into vesicles with NTsand then released with them.#
These can have slow depolarizing effects like LHRH or slow hyperpolarising like opioids.
Their is also NANC or non-adrenergic and non-cholinergic. these actually act on different receptors to alter the post-synaptic response. purinergic ATP has an excitatory effect on Alpha 2 receptors, and VIP and SP have inhibitory and excitatory effects of M2 respectively
in addition peptides can actually alter the flow through an LGIC. idea of how BZs work
What is morphine?
Morphine is an opioid drug
Its unique as when given as an epidural it can have a direct effect on the CNS without systemic effects as it act on GPCR like receptors on the spine.
Other molecules, are substance P- excitatory
and Adenosine inhibitory
What are the 3 main Ionotropic Glutamate receptors?
AMPA: allows Na+ influx and mediates most of the excitatory glutamate in the CNS. expressed on atrocytes and key to their communication.
Kainate: Fulfills the role of AMPA and can enhance or reduce transmitter release.
NMDA: Can enhance or reduce s release. mediates the delayed current, due to the need to remove a Mg2+ block. Hence they tend to co-exist with ampa whos depolarization achieves this. Nmda calcium entry is what mediates LTP or LDP, which plays a large role in pain and the hippocampal role in memory.
Outline the glutamate action via metabotropic receptor?
The glutamate GPCR is a part of family C. it has a extracellualr N-terminus which acts like a venus fly trap to bind glutamate.
There are 3 variations: 1: this has a post-synaptic effect and is related to increasing the intracellular calcium levels, modulating the activity of ionotropic calcium channels.
2-3 have mostly pre-synaptic effects and act as auto receptors to reduce release.
