Ligand gated ion channels

attacks the neuronal ion channel, deadly, and fast-acting 

• affects the voltage gated Na+ channel
• -toxins are used as experimental tools 

batrachotoxins, veratridine, and aconitine 

it blocks inactivation, causing channels to always open 

inactivates channel 

inactivates channels 

conformational change in the protein 

• occurs in discrete area of channel, leading it to open; entire channel changes
• -follows a ball-and-chain mechanism

nt or hormone binding 

binding of the two causes 2nd messenger to activate a protein kinase that phosphorylates a channel that opens it.  

• 1. when there's changes in the membrane potential 
• 2. mechanical deformation 
• 3. selectivity by charge (positively lined allow anions thru; negatively lined allow cations thru) 

• ions flow from high to low conc (down gradient)
• -cannot be coupled to energy source (no energy required/used)
• -move ions /H20 thru gradient, otherwise, ions wont flow thru
• -small highly selective pores in cell membrane 

everywhere; present in almost every cell 

• transport of ions and H2O
• -regulate electrical potential across membrane 
• -signaling 

• open (conducting) and closed (nonconducting) 
• *part of channel structure /external particle blocks; otherwise, open channel 

means they are always open and cannot be closed 

• can go through conformational change when...
• there is voltage across cell membrane, 
• there's a ligand, 
• when there's mechanical stimulus, heat

atomic, electric and hydrophobic forces 

• glutamate receptors
• nicotinic acetylcholine receptor, 
• vanilloid receptor family (TRPV) 

• gated by ligand, present on outside of cell, whihc are receptors
• -all are nonselctive cation channels
• -mediate effects of neurotransmitters 

• have pentamer of protein subunits
• 2 binding sites for acetylcholine - when bound alters configuration and cause internal pore to open 
• allows Na+ ions to flow down electrochemical gradient into cell 

• corresponds to sets of protein subunits of the same functional class
• gene families for each majoe a, b, and y 

• are scattered over many chromosomes, there's occasional clusters 
• eg. GABAa receptor a1, a6, b2 and y2 are all close together at q31-35 on chromosome5 

no consistency in lengths 

• timing gene expression during development
• mechanism of expression of gene expression of neurons and types of neurons 
• regulation of receptor gene expression during synapse formation 

**lilltle known aobut mechanism involving environmental singals 

no, not all; some use other initiator elements 

RNA pol II and plethora of ancillary factors

need additiolnal seq-specific interactions of various txn factors with cis-acting enhancer and silencer elements 

• 1. global silencing of neuronal genes in non-neuronal cell types 
• 2. silencing at fine-tuning level to restrict expression of neuronal genes to a subset of neurons 

• have no TATA or CAAT start sites;
• GC-rich with multiple txn start sites within CpG island 
• promotors ocntian overlapping Sp1 and GSG recog sites near major txn start sites and NSR silencer 
• -NSR sequence in NR1 and GluR2 genes have small modulatory effect with respect to neuronal specificity of expression 

a site of mediation of stimulatory effects on gene expression of signaling pathways initiated by neurotrophic factor, GDNF and BDNF

GDNF and BDNF

occurs a lot during development

not very widespread among RNA transcripts of LG ion channel receptors 

means more than just a difference in short aa sequence that may regualte post-translational modification processes, such as phosphorylation and glycosylation sites 

• variatns of same receptors subunits 
• eg: AMPA 

• flip and flop
• correspond to alternative inclusion of either of 2 adjacent exons (exons 14 and 15 in GluR2 gene)

• flip forms of most subunits desensitize more slowly and lesser degree than flop forms;
• easily displayed probed with various agents 

ADAR1 and ADAR 2

• oxidative deaminated then inosine
• inosine bp like G causes change to codon, causing different aa in translated protein 

• formation of ds structures involving intronic sequences, which bp with exonic sequences to be edited
• other protein factors may be involved cuz some cells express ADARS but cannot edit

• GluR Q/R editing and 
• GluR R/G editing 

• S RNA editing sites: GluR2, 5,6: leads to replacement of gln codon (CAG) by arg codon (CIG=CGG) and insertion of arg (R) to TM domain 
• occurs in M2, has low Ca2+ permeability; low single channel conductance, linear rectifying properities 

• GluR2, 3, 4 undergo editing at R/G sites in exon 13; just N-term to flip flop regio nof alt splicing 
• reduces sensitization and accel recover 

• not exactly known; 
• so shouldnt make inferences about levels of protein subunits from mRNAs 

removal of 5'UTR thats involved in putative stem-loop structure results in sig. disinhibition of translation 

broad region containing a repeat sequence near 5' end of mRNA, which may affect various txn start sites differentially

• extensively phosophorylated and glycosylated
• -kinases known to phosphorylate LGICs

PKA, CaMKII, PKC

• PKA phos AMPARs causes increase channel open time or the P(O) state 
• CaMKII phos AMPARs corre with increase synaptic resonses (synaptic plasticity)
• phosphorylation of receptors is corr. with activity 

• proximity to of LGICs to kinases and phosphatases in high [protein] milieu
• **refer to examples

• oligomannosidic glycans + complex oligosaccharides 
• increase efficiency of receptor asembly and cell-surface density of GABAaRs, but not essential for these processes
• strongly required for ER exit of assembled GlyR and nAchR
• appears that glycosylation - similar quality control over all receptors 
• no clear role for glycosylation of LGICs

• peptide synthesis
• folding 
• post-translational modifications 
• insertion to ER 
• strict selectivity is required os that only certain combinations of the correct subunits are oligomerized and target to plasma membrane via Golgi 

• nAchR: aabyS
• aby trimers form and recruit B and then 2nd  a subunit 

GlyRs, aaaBBB

involves targeting correct sites on membrane 

LGICs are held in hynamic relatinship (lateral diffusion) with a protein complex by multiple interactions with certain proteins playing key roles in receptor clustering and retention 

BlyR

nAchR

with intracellular M3-M4 loop of nAchR and mediates action of agrin-stimulated signaling pathway that drives nAchR into synapses 

they alternate and assoicate with the clustering 

• becomes extensively inolved with scaffolding proteins, cytoskeletal anchoring proteins, and signal transduction proteins 
• C.f., PSD complex
• receptors are removed fr cell surface and from synapses in response to environmental signals as well for receptor production 
• -signal adaptor proteins (eg. AP-2, arrestin, ubiquitin) 

• membrane invagination, endocytosis --> early endosomes --> recycle to plasma membrane or delivered to late endosomes for sorting --> recycled via trans-Golgi to plasma membrane or to lysosomes for degradation 
• -all events involve protein-protein interactions

• block ubiquitinization 
• or shuttling them to recycling