Ligand Gated Ion Channels Ionotropic Receptors 1 Transmembrane

Ligand Gated Ion Channels/ Ionotropic Receptors 1. Transmembrane ion channels (Na+, K+, Ca 2+, Cl-) involved in synaptic transmission 2. Binding of ligand (neurotransmitter) opens channel and allows ion flow down electrochemical gradient resulting in either depolarization (activation) or hyperpolarization (inhibition) 3. Ligand-gated ion channels consist of multiple subunits (3 -5) 4. Some subunits contain N-terminus region that binds ligand 5. All subunits contain transmembrane domains that form a channel

Ligand Gated Ion Channel Families Cys-loop receptors 1. Cationic a. Serotonin receptors (5 -HT 3) b. Nicotinic Acetylcholine receptors (NACh. R) c. Zinc activated ion channel (ZAC) 2. Anionic a. GABAA (g-amino butryic acid) b. Glycine 3. Typically these receptors are pentameric, with the subunits coming together to form the channel. 4. The subunits have a characteristic Cys bond in the N-terminus (Cys-loop). 5. The subunits have four transmembrane domains, with a large 2 nd intracellular loop that is thought to regulate desensitization, and response to ligand.

Nicotinic Acetylcholine Receptor Classical NACh. R Structure NACh. R 1. 10 a subunits, 5 b, 1 each g, d, e 2. Further subclassified a. Muscle type: a 1, b 1, g, d, e b. Neuronal: i. Type I a 9, a 10 ii. Type II a 8, a 7 iii. Type IIIa: a 2, a 3, a 4, a 6 iv. Type IIIb: a 2, a 4 v. Type IIIc a 3, a 5 3. Canonical structure a, a, b, d, g 4. Clearly, many combinations are possible in addition to the canonical 5. Channels are not necessarily ion specific, can allow flow of Na+, K+, and even Ca 2+ 6. (a 3)2(b 4)3 found in autonomic ganglia/brain 7. (a 4)2(b 2)3 found reward centers in brain 8. (a 7)5 brain

Nicotinic Acetylcholine Receptor Signaling Examples of NACh. R subtype signaling 1. (a 3)2(b 4)3/(a 4)2(b 2)3 linked to activation of PI 3 -kinase and Ras/MAPK, PKA signaling 2. (a 7)5 linked to activation of PKA 3. (a 9)5 linked to activation of PI 3 kinase and modification of estrogen receptor function

Ligand Gated Ion Channel Families Glutamate Receptors 1. NMDA (N-methyl-D-aspartate) receptor 2. AMPA (α-amino-3 -hydroxy-5 -methyl-4 isoxazolepropionic acid) receptor 3. Kainate receptor Properties 1. They bind the neurotransmitter glutamate 2. These receptors form tetramers 3. Receptor structure: a. Amino-terminal (N-terminal) domain (ATD) involved in tetramer assembly b. Extracellular ligand binding domain (LBD) – formed by the N-terminal tail and the extracellular loop between helices 3 and 4 from the transmembrane domain c. Transmembrane domain with 3 transmembrane helices (1, 3, 4), and one ½ helix (2). d. Ionotropic glutamate receptors allow Na+ and Ca 2+ (to a lesser extent) into the cell.

Glutamate Receptor Signaling Glutamate 2+ Na+ Ca Glutamate receptor signaling 1. Two types of glutamate receptors a. Metabolotropic – GPCRs that signal through Gq (m. Glu. R 1/5) or Gi/o b. Ionotropic – Ligand gated ion channels 2. Like NACh. R, the ionotropic glutamate receptors (AMPA, NMDA, KAR) can act as scaffolds to recruit signaling proteins

Ligand Gated Ion Channel Families P 2 X receptors 1. Activated by ATP 2. Form trimers, with each monomer consisting of two transmembrane helices a large extracellular loop containing a ligand binding domain, with the N- and C -termini on the cytoplasmic side. 3. Mediate Ca 2+ entry

P 2 X Receptor Signaling P 2 X receptor signaling 1. Like the glutamate receptors, there are multiple receptor types that bind to and are activated by purines like ATP and adenosine 1. P 2 X ligand gated ion channels 2. Purinergic recptors – GPCRs that bind ATP, ADP, UTP, UDP 3. Adenosine receptors GPCRS 2. Like NACh. R, the ionotropic glutamate receptors (AMPA, NMDA, KAR) can act as scaffolds to recruit signaling proteins