Bear et al. 2001, Neuroscience, 2nd ed. The Impact of Neurotransmitters Metabotropic Receptors.

Bear et al. 2001, Neuroscience, 2nd ed. The Impact of Neurotransmitters Metabotropic Receptors can regulate ion-channels or enzymes. α β γ α β γ

Bear et al. 2001, Neuroscience, 2nd ed. The Impact of Neurotransmitters Ion-channel modulation via metabotropic receptor binding. α β γ

G-protein modulation of channels can be either “direct” or “indirect”

Adrenergic depression of I Ca is clearly voltage dependent Bean, BP, Nature (1989) 340:

Opioid depression of I Ca is also clearly voltage dependent Bean, BP, Nature (1989) 340:

“Fast and voltage-dependent depression of I Ca can be described by the “willing/reluctant” model Bean, BP, Nature (1989) 340:

Many neurotransmitters depress I Ca via a fast, voltage-dependent mechanism

The “willing/reluctant” mechanism of Ca 2+ channel modulation The effector subunit of the G  /  heterotrimer is the  dimer

Regulation of Ca 2+ channels directly controls neurotransmitter release

G  q Stimulation of G q/11 -coupled receptors results in PLC activation, PIP 2 hydrolysis and release of several second messengers GPCR A DAG ER IP 3 PAAA PKC

Inhibition of channels isolated in cell-attached patches by bath- applied agonist implies a “diffusible messenger” Zhang et al., Neuron : modified scheme of Soejima and Noma, Acetylcholine (oxotremorine) Ca 2+

Ca 2+ channels are sensitive to PIP 2 in the membrane, and G q/11 -mediated muscarinic suppression of I Ca involves depletion of PIP 2. PLC  -PH translocation

Kir2.1Kv7.2 K452 R459 R461 R463 R467 R189 K219 R218 R228 A B β1β1 β2β2 β3β3 β4β4 β6β6 β7β7 β5β5 K ir channels and Kv7 channels share a similar PIP 2 -binding motif Structural homology model of PIP 2 -binding loop of Kv7.2, docked with a PIP 2 analog

G  q Stimulation of G q/11 -coupled M 1 receptors inhibits M-type K + and N-type Ca 2+ channels via PIP 2 depletion M1RM1R A IP 3 X M/Ca 2+

Ca 2+ channels are heavily regulated

Calmodulin mediates both Ca 2+ -dependent inactivation and facilitation

Downloaded from: StudentConsult (on 17 December :22 PM) © 2004 Elsevier Synaptic inputs can add together

Figure 4-10 A, Spatial and temporal summation at a postsynaptic neuron with two synaptic inputs (1 and 2). B, Spatial summation. The postsynaptic potentials in response to single action potentials (aps) in inputs 1 and 2 occur separately and simultaneously. C, Temporal summation. The postsynaptic response to two impulses in rapid succession in the same input. Downloaded from: StudentConsult (on 17 December :22 PM) © 2004 Elsevier Short-term facilitation occurs upon rapidly repeated stimulation of synapses

Long-Term Potentiation May Underlie Learning and Memory Malenka, R.C. and Nicoll, R.A., Science, Vol 285, Issue 5435,

Bursting controlled by Ca 2+ -activated K + channels Time (s) EMEM light =[Ca] 50 mV Recording from a secretory neuron of Aplysia shows Ca 2+ entry during burst, triggering repolarization and termination of burst. (Gorman & Thomas, 1978)  0.1% Ca 5 s Bursting pacemaker slow after- hyperpolarizations

Electrical activity of beta cell in islet: high glucose Depolarize membrane V-gated Ca 2+ channels open Membrane potential 10 mV 10 sec Time Mouse pancreatic islet in 11 mM glucose (200 mg/dl) beta cell Ca 2+ enters exocytosis of insulin granules (Cook, 1980) Neuroendocrine cells secrete hormones like neurons secrete neurotransmitters

Regulation of secretion in electrically excitable cells: Depolarization Ca 2+ entry through Ca 2+ channels Pituitary somatotrope GHRHGrowth hormone Synapse (presynaptic) Action potentialNeurotransmitter Chromaffin cell AChAdrenaline Pancreatic  cell GlucoseInsulin Sperm Egg jellyAcrosome reaction Secretion of Depol --> Ca 2+

Membrane potentials Roles of ion channels Electrical signals Ca 2+ signals Ion transport Cell Membrane Out In Ions Three roles channels