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 βγ

α βγ

Bear et al. 2001, Neuroscience, 2nd ed.

The Impact of Neurotransmitters

Ion-channel modulation via metabotropic receptor binding.

α βγ

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

Adrenergic depression of ICa is clearly voltage dependent

Bean, BP, Nature (1989) 340:153-156

Opioid depression of ICa is also clearly voltage dependent

Bean, BP, Nature (1989) 340:153-156

“Fast and voltage-dependent depression of ICa can be described by the “willing/reluctant” model

Bean, BP, Nature (1989) 340:153-156

Many neurotransmitters depress ICa via a fast, voltage-dependent mechanism

The “willing/reluctant” mechanism of Ca2+ channel modulationThe effector subunit of the G/ heterotrimer is the dimer

Regulation of Ca2+ channels directly controls neurotransmitter release

Gq

Stimulation of Gq/11-coupled receptors results in PLCactivation, PIP2 hydrolysis and release of several second messengers

GP

CR

ADAG

ER

IP3

PA AA

PKC

Inhibition of channels isolated in cell-attached patches by bath-applied agonist implies a “diffusible messenger”

Zhang et al., Neuron. 2003. 37:963-75

modified scheme of Soejima and Noma, 1984.

Acetylcholine(oxotremorine) Ca2+

Ca2+ channels are sensitive to PIP2 in the membrane, and Gq/11-mediated muscarinic suppression of ICa involves depletion of PIP2.

PLC-PH translocation

Kir2.1 Kv7.2

K452

R459

R461R463

R467R189

K219

R218

R228

A B

β1

β2β3

β4

β6

β7β5

Kir channels and Kv7 channels share a similar PIP2-binding motif

Structural homology model of PIP2-binding loop of Kv7.2, docked with a PIP2 analog

Gq

Stimulation of Gq/11-coupled M1 receptors inhibits M-type K+ and N-type Ca2+ channels via PIP2 depletion

M1R

A

IP3

XM/C

a2+

Ca2+ channels are heavily regulated

Calmodulin mediates both Ca2+-dependent inactivation and facilitation

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© 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.

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© 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, 1870-1874

Bursting controlled by Ca2+-activated K+ channels

0 40 80Time (s)

EM

light=[Ca]

50 m

V

Recording from a secretory neuron of Aplysia shows Ca2+ entry during burst, triggering repolarization and termination of burst. (Gorman & Thomas, 1978)

0.

1% C

a

5 s

slow after- hyperpolarizations

Electrical activity of beta cell in islet: high glucose

Depolarize membrane V-gated Ca2+ channels open

Mem

bran

e po

tent

ial

10 m

V

10 secTime

Mouse pancreatic islet in 11 mM glucose (200 mg/dl)

beta cell

Ca2+ enters exocytosis of insulin granules

(Cook, 1980)

Neuroendocrine cells secrete hormones like neurons secrete neurotransmitters

Regulation of secretion in electrically excitable cells:Depolarization Ca2+ entry through Ca2+ channels

Pituitary somatotropeGHRH Growth hormone

Synapse (presynaptic)Action potential Neurotransmitter

Chromaffin cellACh Adrenaline

Pancreatic cellGlucose Insulin

SpermEgg jelly Acrosome reaction

Secretion of

Membrane potentials

+

+

Roles of ion channels

Electrical signals Ca2+

signalsIon

transport

Cell Membrane

Out

In

Ions

Three roles channels