Neuronal Metabolism Flashcards
What 2 types of intracellular signalling can occur?
2nd Messenger signalling (single molecules causing a response such as cAMP and cGMP, Ca2+, NO)
Signalling pathways
(MAP kinase pathways)
What are some physiological roles for intracellular neuronal Ca2+?
- role in synaptic transmission (in mediating neurotransmitter release)
- role in regulating plasma membrane channels (inhibiting or making neurones excited)
- role in modulating synaptic plasticity and learning
- mediate changes in gene expression
- involved in neuronal development
- neuronal survival (dependent on Ca/ mitochondria relationship)
What is the involvement of intracellular Ca in neuronal pathology?
- mediator of cell death (necrosis, ischemia (stroke), traumatic brain injury)
- potential modulator of neurodegenerative processes (Ca2+ hypothesis of Alzhemier’s disease)
What conc of Ca is seen extracellularly compared to in the cytosol?
1-2mM outside of the cell
100nM in the cytosol
(100 nM in the nucleus, 0.5mM in the ER, 0.2-20 uM in the Mitochondrion)
What 2 paths are there for Ca entry into the cytosol?
Ca entry from extracellular space or intracellular stores (endoplasmic reticulum)
What channel structures are seen in the plasma membrane for the extracellular Ca pathway?
- voltage operated Ca channels
- receptor operated channels
- store operated channels
What structures are seen in the ER plasma membrane for the intracellular Ca pathway?
- ryanodine receptors that mediate the process of calcium-induced Ca release (CICR)
- InsP3 receptor release
Which segments in the alpha 1 subunit is responsible for voltage sensitivity (how does it work) and which is responsible for Ca specificity?
Voltage sensitivity is seen in Segment 4 - the depolarisation of the plasma membrane will activate S4 which will generate the opening of the channel and the loop between segment 5 & 6 are for Ca specificity.
What is the structure of the alpha 1 subunit in voltage operated Ca channels?
Consists of 4 major transmembrane domains (I-IV) which each consists of 6 transmembrane helices.
What are the differences between the 3 major families of alpha 1 subunits (Cav1 -3)?
Difference between the amino acids composition in the alpha 1 subunit and the binding of 3 other auxiliary subunits (alpha2 bound to delta, gamma and beta)
How are Ca Channels distributed in both central and sensory neurons?
- CAV2.1 and CAV2.2 channels are present at pre and post synaptic terminals to modulate response
- T-type channels are present in dendrites, where they participate in oscillations
- L-type channels participate in excitation-transcription coupling
How do Receptor/Ligand operated Ca channels work?
2 parts of the channel
1 - one part is the receptor that is complimentary to the ligand
2- Second part is the making up of the channel
- As it binds structural modifications occur to activate the channel
What is the most important neurotransmitter in the biological brain?
Glutamate
What two types of receptors will glutamate bind to?
Ionotropic receptor
- ion related receptor
- as the neurotransmitter binds to the binding site, ions will flow through the channel
Metabotropic receptor
- when glutamate binds to the binding site, this will activate an intracellular signalling protein (most likely G protein coupled) generating Ca release or cAMP release - a 2ndary messenger
What functional classes in ionotropic receptors do not exist in the human brain?
NMDA, AMPA and Kainate
What is the structure of a glu ionotropic receptor unit?
- smaller than Ca channel
- 4 transmembrane domains
- one cannot go through, generating the M2 loop
- amino end of protein is extracellular but carboxy is intracellular
- amino end has glu and modulator binding site
- carboxy end has the channel forming pore (M2 region)
How many receptor units needed for 1 glutamate receptor?
4
- tetradimer
What is Ca permeability dictated by in the M2 loop?
Dictated by 1 a.a change
- if R present then no Ca permeability (AMPA/R Receptors)
- if N present then high permeability (NMDA receptors)
- if Q present then low Ca permeability (AMPA receptors)
What is needed for Ca removal to the extracellular space?
- plasma membrane Ca ATPase (due to huge conc gradient so needs a lot of energy- active)
- Na-Ca exchanger
(Na will come in, the energy brings in will be used to push Ca out)
What is needed for Ca removal to the intracellular stores?
- SERCA , Sarco(Endo) Plasmic Ca ATPase
What are the 3 spatial functional domains of Ca signalling?
Nanodomains: - high conc, short distances such as activating exocytosis Intermediate domains: - medium conc, larger distances - influence another synapse of dendrite Long range domains: - low conc, larger distances - Ca enter plasma membrane into the nucleus for gene expression / other activations
What are Ca buffers?
Proteins that bind to free Ca2+ ions. With a buffer, the concentration will decrease over a certain distance compared to if there was no buffer.
- when present in cytosol will bind to Ca
- in cytosol it is parvalbumin and calbindin-D9k
- in intra-organelle it is calreticulin
What are Ca sensors?
- proteins that binds to free Ca and causes a change of conformation that then triggers a range of responses
(e. g. when Ca binds to Calmodulin, an EF domain is formed)
Calcium-calmodulin complexes
Mediates Ca sensitive reactions - involved in metabolism, exocytosis and many other roles
