LECTURE 10: SYNAPSESIII: METABOTROPIC RECEPTORS AND SECOND MESSENGERS REQUIRED READING: Kandel text, Chapter 13 IONOTROPIC RECEPTORSMETABOTROPIC RECEPTORS STRUCTUREMulti-subunit channelsUsually 7-TM GPCRs KINETICS OF CHANNEL MODULATION msec100 msec to days NT RECEPTOR TYPE: PRODUCTION OF 2ND MESSENGER Almost always NOYES EFFECT OF NT ON CHANNELS OPENOPEN or CLOSE LOCATION/TYPE OF AFFECTED CHANNELS Post-synaptic ligand-gated channel Post-synaptic channel, Voltage-gated channels, Resting channels NUMBER OF AFFECTED CHANNELS 1 NT molecule = 1 opened channel 1 NT molecule = MANY opened channels

SECOND MESSENGER SYSTEMS OF METABOTROPIC NT RECEPTORS

RECEPTOR-ACTIVATED G-PROTEIN CYCLE: G s and cAMP

PHOSPHATIDYL INOSITOL BIS-PHOSPHATE IS SOURCE OF SEVERAL SECOND MESSENGERS

Gq-ACTIVATED PHOSPHOLIPASE-C GENERATES TWO SECOND MESSENGERS

MANY SECOND MESSENGERS ACTIVATE SERINE/THREONINE PROTEIN KINASES Each S/T-protein kinase phosphorylates exposed serine or threonine residues within a consensus sequence. E.g Arg-Arg-Xxx-Ser-Xxx HO-P=O O- -O- ATPADP PKA

G  -ACTIVATED PHOSPHOLIPASE-A GENERATES ARACHIDONIC ACID: AA METABOLISM CREATES SECOND MESSENGERS

SEROTONIN CLOSES S-TYPE POTASSIUM CHANNELS IN APLYSIA SENSORY NEURONS

SINGLE CHANNEL RECORDINGS FROM CELL-ATTACHED PATCH I pipet 0 CLOSE OPEN CLOSE OPEN CURRENT MONITOR CHANNEL STATUS Pipet Solution Same as Extracellular Bath

SINGLE CHANNEL RECORDINGS FROM EXCISED INSIDE-OUT PATCH CURRENT MONITOR pipet extracellular solution bath intracellular solution

CELL-ATTACHED PATCH AND INSIDE-OUT PATCH RECORDINGS SHOW SEROTONIN ACTS THROUGH cAMP SECOND MESSENGER TO CLOSE S-TYPE K + CHANNELS

CELL-ATTACHED PATCH AND INSIDE-OUT PATCH RECORDINGS SHOW FMRF-AMIDE ACTS THROUGH AA SECOND MESSENGER TO OPEN S-TYPE K + CHANNELS

MUSCARINIC ACETYLCHOLINE RECEPTORS CLOSE M-TYPE POTASSIUM CHANNELS: TRANSFORMATION OF EPSP-INDUCED FIRING RESPONSE

ACETYLCHOLINE OPENS GIRK VIA NON-DIFFUSIBLE G 

IONOTROPIC NMDA RECEPTORS GENERATE CALCIUM SECOND MESSENGER: CALCIUM-CALCINEURIN PATHWAY OPPOSES DOPAMINE-cAMP PATHWAY

METABOTROPIC SECOND MESSENGERS cAMP and CALCIUM INDUCE SLOW ONSET LONG-LASTING SYNAPTIC MODIFICATIONS THROUGH NEW PROTEIN SYNTHESIS Calcium influx through NMDA receptors into post-synaptic dendrite induces protein synthesis from dendritic mRNAs, resulting in slow-onset long-lasting post-synaptic modification cAMP production by serotonin receptor-Gs system in presynaptic axon induces specific gene transcription and translation, resulting in slow-onset long-lasting pre-synaptic modification

NEXT LECTURE: NEUROTRANSMITTERS AND RELEASE READING: Kandel text, Chapters 14, 15