chapter 9 - synaptic NT-gated receptors Flashcards
9.1. [synaptic NT-gated receptors] what are the working principles and structure-function of synaptic NT gated receptors?
Synaptic NT-gated receptors
> a.k.a. ionotropic receptors – metabotropic receptors: use second messengers
> decode chemical signals into electrical responses
> ionotropic glutamate, Ach and 5-HT receptors are permeable to cations - > excitation (depolarization) of postsynaptic cell
> GABA and glycine ionotropic receptors are permeable to anions –> hyperpolarization of postsynaptic cell
> Ach, 5-HT, GABA and glycine ionotropic receptors belong to the Cys-loop receptor superfamily –> ionotropic glutamate receptor superfamily
structure of cys loop receptors
> extracellar domains (ECDs) are composed of inner and outer B-sheets and one a-helix per subunit
> transmembrane domains (TMDs) are formed by 4 a-helices/subunit
Cys-loop receptor gene family
> pentameric ligand-gated ion channels with a highly conserved structural signature: a loop formed by a disulfide bridge in the extracellular domain
* nicotinic acetylcholine receptors (nAchR)
* type-3 5-hydroxytryptamine receptors (5HT,R)
* type A and C y-aminobutyric acid receptors (GABAA/cR)
* glycine receptors (GlyR)
> receptor subunit composition generates complexity and diversity, e.g.
* GABAA/cRs: 8 subunit families (a1-6; B1-3; v1-3; 6; €; л; 0; p1-3)
- -> 19 possible subunits!
* nAchR: 5 subunit families (a1-7, 9, 10; B1-4; v; 6; €)
- -> 16 possible subunits; subunit compositions at NMJ:
embryonic: alpha 2 beta gamma ohm ; adult: alpha 2 beta epsilon ohm
Cys-loop receptor gene family: functional aspects
> efficacy of synaptic transmission relies heavily on receptor subunit composition and the number of receptors in the PSD
> receptor-associated molecules provide a scaffold near the surface membrane that influences receptor trafficking through post-translational modification (mainly phosphorylation) of receptors and their associated molecules, receptor expression, and function can be regulated.
> receptor activation is mediated by ligand binding, inducing structural rearrangements around the ligand-binding site which are transmitted through the ECD to the TMDs to initiate ion channel opening.
> ion selectivity filter: at either end of the ion channel, charged rings of residues regulate ion conductance. For nAchRs and5HTyRs, the rings are negatively charged, selecting for cations _, for GABA cRs and GlyRs, the rings are net positively charged and thus anion selective
ionotropic glutamate receptors
> 4 families of iGluR subunits; each subunit is encoded by a distinct gene and there is no mixing between subunit families
> excitatory postsynaptic current is typically mediated by members of the AMPA and NMDA families
> KainateRs are found both on the pre-and postsynaptic compartments and have a more modulatory role
> DeltaRs are incapable to gate an ion channel following ligand binding, and are thus “electrically silent”. Their function is poorly understood.
> Apart from deltaRs, which mainly form homomeric receptors, differential coassembly of subunits generates a large number of iGluR receptor subtypes
> sigmiloR as the cys- loop
9.2. [synaptic NT-gated receptors] understand and explain the factors that influence the function of synaptic NT-gated receptors
Modification of iGluRS -, further diversity
> posttranscriptional modifications:
* alternative splicing ~y. ENCODE SINGLE GENED
* RNA editing: leads to single amino acid changes with important functional consequences
> posttranslational modifications:
* phosphorylation: by a variety of intracellular kinases, including
PKA, PKC, CamKIl, Sre and Fyn kinases. Phosphorylation, AGnOVE/ ADD & regulates receptor trafficking, localization, binding to intracellular Proteins and in some cases channel activity
* palmitoylation ( SEE EROLyPOSIS LECarRE
* SUMOylation (SimiLAR TO UBITIFIQUATION)
subunit composition and modification result in unique functional properties of a given receptor
the intracellular tails of iGluR subunits also directly interact with numerous other proteins e.g. scaffolding proteins
Sumoylation is a post-translational modification process. It is analogous to ubiquitylation in terms of the reaction scheme and enzyme classes used, but rather than conjugation by ubiquitin, sumoylation involves addition of SUMOs (small ubiquitin-like modifiers).
> iGluRs form tetramers; each subunit
consists of:
* a large extracellular N-terminal domain (NTD)
* an agonist-binding domain (ABD)
* a transmembrane domain (TMD) that forms the ion channel
* a cytoplasmic C-terminal domain (CTD)
structural mechanisms of iGluR activation (see pic)
> 1 iGluR ABDs display a clamshell-like fold - agonists bind to the interlobe cleft - cleft closure - 2 tension on the ABD-TMD linker - channel gate opening
> competitive antagonists: bind to the ABD, but lock it in an open cleft conformation (doesn’t close cleft but glu can’t bind and receptor channel stays closed)
> partial agonists: induce less domain closure than full agonists, leading to submaximal channel opening
9.3. [synaptic NT-gated receptors] Which iGluR families mediate postsynaptic currents and how can their activity be adapted/modulated?
*-iGluR receptor families mediating postsynaptic currents: AMPA and NMDA receptors.
-In general, receptor activity is modulated by the intrinsic activity of the receptors, and by their surface expression levels. How are these modulated?
1. subunit composition: differential co-assembly of subunits generates a large number of iGluR receptor subtypes.
2. posttranscriptional modification of iGluR subunits:
-alternative splicing
-RNA editing, giving rise to single amino acid changes with important functional consequences.
3. posttranslational modification of iGluR subunits:
-phosphorylation: regulates receptor trafficking, localization and binding to intracellular proteins and in some cases receptor activity.
-palmitoylation
-SUMOylation
