Lecture 11- Modulation of neuronal functions by metabotropic receptors Flashcards
What is the additional info about desensitisation?
- desensitisation= the activation of the G protein causes phosphorylation of the receptor itself, this happens generally among G coupled receptors, the sites of binding become sites for arrestin and those prevent binding or make it more difficult= this is to prevent overstimulation, inefficient at activation the G protein
2: second method= the arrestin and phospho promote internalisation of the receptor, message that goes on all the time (a housekeeping mechanism) this process is sped up due to arrestin and phosphorylation tachylapsis= law of diminishing returns -arrestin interfreres with the coupling of the GCPR and GCP
What are the 3 ways in which the metabotropic receptors regulate ion channels?
- Coupling by G-protein directly to an ion channel
- Coupling by G-protein to a second messenger system, where the 2nd messenger (eg cAMP, cGMP) directly regulates an ion channel
- Coupling by G-protein to a second messenger system, leading to ion channel phosphorylation
- in most cases the G protein binds to an enzyme
- cAMP and cGMP usually do not have all or none effect
What are PI, PIP and PIP2?
- these molecules= membrane phospholipids, tend to occur on the cytoplasmic part of the membrane, these are the inositol (6 carbon ring, type of sugar)
- the basic structure is based on the 3 carbon glycerol molecule with three hydroxyl groups and have fatty acids that form the hydrophobic core, one of the acids is polar acid and that sticks out into the cytoplasm (phosphoric acid) to which another molecule is attached (Inositol) which is used as a signalling molecule, used in several forms, when phosphorylated twice it is the PIP2 which is commonly occuring in membranes, as two enzymes act on it in response to G proteins
What is the interaction of Phopsholipase C and PIP2?
- Phospholipase C cleaves PIP2 into PIP3 and diglycerol
- PIP2 is a substrate for PI3-K (enzyme) as well, so attaches another phosphate to PIP2 to change into PIP3 which unlike PIP2 is an activator, can activate Kinase protein B
What is this?
- different types of receptors
- one of the serotonin receptors is metabotropic
- mostly ionotropic but some are metabotropic
What are the characteristics of neuromodulatory systems?
• Small groups of neurons, mainly in the brainstem, with vast projections to other parts of the CNS • They often have profound effects on function and behaviour • Small-molecule neurotransmitters • Usually G-protein coupled receptors -also called nuclei in the brainstem -hindbrain(medulla, pons and cerebellum) or the midbrain, everything anterior to it is the forebrain (the thalamus etc.) -the nuclei are small but they project quite widely, can have many thousands of neurotransmitter terminals, can modulate over vast areas -use mostly small molecules (dopamine etc.) and use G protein coupled receptors
What does the cholinergic neuromodulatory system in the basal forebrain consist of?
- there are two systems, one in the basal forebrain
- It consists of several contiguous groups (nuclei) of magnocellular cholinergic neurons. From rostral to caudal, these are:
1. Septum
2. Diagonal Band (of Broca) (horizontal and vertical)
3. Basal Nucleus (of Meynert) - small number of neurons in each of these, but their axons spread very far, have effect on every cell in the cerebral cortex and the neocortex
What is some more info about the holinergic system in the forebrain?
- septum connected to hippocampus= called septo hippocampal system= cholinergic system, driven by ACh, if you remove the ACh then hippocampus stops, the reverse is true of increasing the ACh
- the basal nucleus innervates essential the whole neocortex: (the cerebral cortex), septum fornix and the hippocampus= make up the septal hippocampal system that is crucial in memory, particularly vulnerable to Alzheimer’s disease, one of the earliest and most severely affected region
What happens when muscarinic M1ACh receptors in the hippocampus are activated?
→ activates phospholipase C (alpha)
→ closure of M-type K+ channels (βγ)
- depolarising and excitatory
- release ACh onto muscarinic receptors, and act particularly on M1 through to M5, but M1 is the most common
- the effect of stimulating these is 2 fold: alpha component activates Phospholipase C (so generate intracellular calcium)
- the beta-gamma subunit binds to potassium channel (the M type K+ channel) which is normally in resting mode (closed) and having no effect, the effect of it is that in response to repeated stimulation it slows down the neuron, it prevents sustained high frequency response, the response will become refractory
- when beta gamma binds to the M type K+ channel it prevents the M type having an efefct so it is like removing a break, it enables the hippocampus to respond to high frequency stimuli in a sustained manner
- the overall effect of ACh is depolarising and excitatory
What is the nature of Acetylcholine release in the brain?
- 90% of cholinergic release sites in the neocortex and hippocampus are not synaptic
- Instead, ACh is released from varicosities, into the ECF
- Cholinergic axons form many branches in the target tissue, and each branch has varicosities spaced about 2.5 microns apart
- Each cholinergic neuron has between 200,000 and 500,000 release sites
- numerous varicosities (close spacing)
- thanks to the potential release sites the few millions neurons can control almost every neuron in the brain
What does the cholinergic neuromodulatory system in the basal forebrain consist of?
- there are two systems, one in the basal forebrain
- It consists of several contiguous groups (nuclei) of magnocellular cholinergic neurons. From rostral to caudal, these are
1. Septum
2. Diagonal Band (of Broca) (horizontal and vertical)
3. Basal Nucleus (of Meynert) - small number of neurons in each of these, but their axons spread very far, have effect on every cell in the cerebral cortex and the neocortex
- septum connected to hippocampus= called septo hippocampal system= cholinergic system, driven by ACh, if you remove the ACh then hippocampus stops, the reverse is true of increasing the ACh
- the basal nucleus innervates essential the whole neocortex: (the cerebral cortex), septum fornix and the hippocampus= make up the septal hippocampal system that is crucial in memory, particularly vulnerable to Alzheimer’s disease, one of the earliest and most severely affected region
What is this?
- Acetylcholine Release in the Brain varicosity
- release- dillution- ECF av= axonal varicosity
- even astrocytes respond to this release
- sp= dendritic spine
What is this?
-the Septo-Hippocampal System: An important function of the Cholinergic Basal Forebrain
What are the types of neuromodulatory systems? (5)
- dopamine
- acetylcholine
- serotonin
- noradrenaline
- acetylcholine (2 acetylcholine ones)
What is the main role of the dopamine neuromodulatory system?
- Movement, esp. its initiation. Reward and pleasure.
- it is in the Brainstem, midbrain
What is the relationship of the brainstem and forebrain cholinergic systems?
-one in the pons= mainly about sleep and wakefullness and it does conenct to the one in the basal forebrain= the main thing to take from this is that the two systems do connect
What is the dopamine hypothesis of reward?
- “Dopaminergic neurons* are the final common pathway for reinforcement by natural rewards and drugs of abuse”
- The rate of firing correlates not only with the reward, but also with the degree of reinforcement
- * of the VTA
-VTA is in the midbrain and project to the nucleus accumbens (in the forebrain, close to the cholinergic ones we talked about)
What are the consequences of repeated reinforcement of a behaviour?
• Reinforcement becomes stronger with repetition • Stimuli associated with the reward, or that precede or predict the reward, also trigger dopamine release. Thus, the number of cues increase
What is the dopaminergic input to the nucleus accumbens?
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How are dopamine receptors activated?
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What are the initial targets of drugs of abuse?
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