Pre-synaptic modulation A Discussion BH

Table of Contents  A bit of biology  Metabotropic Glutamate receptors  How they work, what they do in context with pre-synaptic modulation  GCPR’s  GCPR’s and their surface expression  Majorly what my paper is about  Discussion elements  Why the included paper is important  What it brings to the table  What I think about it

Disclaimer  Most of this presentation is not going to be slide oriented, but discussion oriented. This presentation will be very short, but I have several discussion topics which I will introduce, which will compose the main part of the presentation  I’m only bringing enough biology to provide context for the rest of the presentation

Family Receptors [11][12] [11][12] Gene Mechanism [11 ] [11 ] Function Agonists & Activators AntagonistsSynapse site Group I mGluR 1 GRM1 G q G q, ↑ Na +, [5] ↑ K +, [5] ↓ glutamate [9] Na + [5] K + [5] glutamate [9] Increase [13][1 4] NMDA receptor activity and risk of excitotoxicity [13][1 4]NMDA receptor excitotoxicity 3,5- dihydroxyphe nylglycine 3,5- dihydroxyphe nylglycine mainly postsynaptic [1 5] [1 5] mGluR 5 GRM5 G q G q, ↑ Na +, [5] ↑ K +, [5] ↓ glutamate [9] Na + [5] K + [5] glutamate [9] Group II mGluR 2 GRM2G i /G 0 Decrease [16] NMDA receptor activity and risk of excitotoxicity [16] NMDA receptor excitotoxicity eglumegad Biphenylinda none A Biphenylinda none A DCG-IV APICA EGLU LY-341,495 mainly presynaptic [15 ] [15 ] mGluR 3 GRM3G i /G 0 Group III mGluR 4 GRM4G i /G 0 Decrease [16] NMDA receptor activity and risk of excitotoxicity [16] NMDA receptor excitotoxicity L-AP4 mainly presynaptic [15 ] [15 ] mGluR 6 GRM6G i /G 0 mGluR 7 GRM7G i /G 0 mGluR 8 GRM8G i /G 0 Metabotropic Glutamate receptors  Metabotropic glutamate receptors are ligand-based channels, that, once activated, initiate g-protein secondary messengers through interaction with g- proteins  Which then go on and initiate signal cascades  There are many different types of metabotropic glutamate receptors  There are many different types of Metabotropic Glutamate receptors  There are 8 major types, divided into three classes

Metabotropic Glutamate receptors: Structure

G-protein: Structure

mGluR7: The focus  mGluR7, which is also called Glutamate receptor, metabotropic 7 (GRM7), serves as an autoreceptor to inhibit neurotransmitter release [1].  A note: I will refer to this GPCR as mGluR7 from here onward  mGluR7 glutamate sensitivity is very low: which means from a probabilistic standpoint, mGluR7 gets activated during sustained release  Plays a role in feedback inhibition  Specifically, mGluR7 inhibits forskolin-stimulated cyclic AMP accumulation in response to agonist interaction, which serves to inhibit neurotransmitter release.  In addition, it serves to modulate glutamate transmission

mGluR7: The focus  Forskolin is a labdane diterpene produced to raise levels of cAMP.  A study of mGluR7 in rats discovered that mGluR7, in the presence of L-glutamate, inhibited the cAMP cascade.  Remember: Several neurotransmitters interact with adenyl cyclase, which hydrolizes ATP into cAMP. cAMP is a secondary messenger, which can interact with a wide host of channels and receptors, which can initiate again a wide array of responses  One of which is neurotransmitter release!

mGluR7: The focus  That being said, what mGluR7 does, put in context, is inhibit neurotransmitter release by gimping the cAMP signal cascade, which in turn limits the scope of neurotransmitter release.  However: Surface expression of mGluR7 is a bit more complicated

The paper I’m introducing [2]

mGluR7 Surface Expression: Important Points  This is what is already known:  Surface expression mGluR7 has been shown in the past to be dependent on PKC phosphorylation of Ser-862 [3].  Specifically: it controls the competitive interaction of calmodulin (CaM) and PICK1 interaction with C kinase  CaM inhibits surface expression, phosphorylation by PKC increases surface expression and receptor binding to PICK1  With this in mind, we know that activity (surface expression) is controlled  There are times when you do and don’t want inhibition of neurotransmitter release: this will be a discussion topic later

What does this paper bring to the table?  I’m not going to discuss the paper point by point, but I am going to introduce the point of the paper.  What this paper theorizes is that the dephosphorylation of Ser-862 likely also plays a major role in the surface expression of mGluR7  Agonist-induced dephosphorylation of mGluR7 is regulated by PP1, whereas NMDA-mediated activity- induced dephosphorylation is not  This means there are multiple pathways for deactivation  PP1 is also important in regulating phosphorylation of mGluR7a and mGluR7b.

Dephosphorylation of Ser-862  Inhibiting PP1 activity causes a robust increase of phosphorylation of mGluR7.  Several tests were conducted in the paper to confirm this, just trust me: they concluded PP1 is, as of now, the prime suspect.  Dephosphorylation of Ser-862 on mGluR7 causes internalization of the receptor through endocytosis  In other words, the receptor is turned off by internalizing the receptor and removing it from the cell surface.

What, then is the importance of this study?  Surface expression of mGluR7 is just as dependent on the dephosphorylation of Ser-862 as it is the phosphorylation by PKC.  The reason being the receptor is endocytosed when dephosphorylated, which inactivates the protein.  This is important because surface expression of mGluR7 can be controlled. There are times when mGluR7 should be expressed, and times where it shouldn’t be as much. This is one of my discussion points.

Discussion Points  I am not sure exactly how to approach this, so I will pose some questions I have, and explain what I think happens/goes on.  Why endocytose mGluR7? Is this the only means of deactivation of the receptor?  Why autocorrect neurotransmitter release? What role does this play in plasticity, as GPCR’s play a major role in?  What is the importance of having multiple pathways to dephosphorylation of Ser- 862 on mGluR7?  Does the kinetics of dephosphorylation play a major role? Would you ever want mGluR7 “turned off” much more quickly or slowly than normal?

References 1. Journal of Biological Chemistry, January 14, 1994, 269 (2): [Main Paper] Journal of Biological Chemistry, June 14, 2013, 288 (14):17544: The Journal of Neuroscience, October 1, 2000, 20 (19):7252–7257