aspectos moleculares y celulares de la función neuronal · diversidad molecular y funcional de...

Diversidad Molecular y Funcional de Canales Iónicos

Aspectos Moleculares y Celulares de la Función Neuronal

Escuela "José A. Balseiro" 2009 Modelado en Neurociencias

Instituto Balseiro - Centro Atómico Bariloche

San Carlos de Bariloche, 5 al 30 de octubre de 2009

Marcela S. Nadal, Ph.DGrupo de Física Estadística e Interdisciplinaria

Yu and Catterall 2004

CANALOMA

de los canales sensibles a voltajey estruturalmenterelacionados

Otros voltage-gated: canales de cloro, receptores ionotrópicos, y metabotropicos?

Hille, 2001; Yu and Catterall 2004

Canal de Sodio

Canal de Calcio

structure of voltage-gated sodium channels

Yu and Catterall 2004

TTX, STX, μ-conotoxins

α-scorpion toxinsea-anemone toxin β-scorpion toxin

P

P

PP

P

PP

P

phosphorilation

β1β2β3β4

mammalian Nav alpha-subunits

TTX location properties and function

S Brain, PNS AP upstrokeS Brain AP upstrokeS Brain, DRG, embr. neuropathic painS DRG, Brain fast act/inact, high threshold, pain S DRG, Brain low threshold, AP upstrokeS sk. Muscle skeletal muscle functionR heart heart functionR PNS (sensory) slow act/inact, low threshold, painR PNS pain sensationR DRG, uterus, glia Na+ / water balance (NaC)

amino acid homology:% identity to NaV1.2.

Hille, 2001

distribución subcelular de canales de sodio Nav

Huang, 2009; Rasband & Shrager, 2000

[Nav]

Nav channels

caspr

Kv channelsaxon

Schwann cell

Huang, 2007

subcellular organization of inputs and ion channels in pyramidal neurons in the neocortex

partially overlapping expression of two different Navsubunits in the AIS of Pyr cells

Nav1.2 Nav1.6

Wu et al., 2009

especialización de NAv en el segmento inicial del axon

Wu et al., 2009

Nav1.2: high thresholdNav1.6: low threshold

simulation of backpropagation of action potentials

Wu et al., 2009

mecanismo de iniciacion de potenciales de accion en el segmento inicial del axon de una neurona piramidal

subcellular targeting of synapses and Nav1.6 channels in cerebellar Purkinje

neurons

persistent and recurrent Na+ currents

TTX

Do& Bean, 2003; Huang, 2009

“open state” during recovery from inactivation

incomplete inactivation (5% of channels)

Do & Bean, 2003

slow inactivation of INa during basal spontaneous activity

79Hz 40Hz

Grieco et al., 2005

mouse β4: aas158-166 of the cytoplasmic tail areKKLITFILKKTREK

voltage-gated Ca2+ channels (VGCC)

Budde, 2002; Catteral, 2008

α1

β

α2

δ

γ

α1

β

δγ

α2

Hille, 2001

Cav α subunit interacts with many other proteins

CaV alpha subunits in vertebrates

adapted from Hille, 2001

ICa at +10 mV from a holding of –50 mV

Budde et al., 2002

burst firingtonic firing

-58 mV

Llinás and Jahnsen 1982

Sherman 2005

oscilaciones talamocorticales

Steriade, 2004

(TRN)

ACh, NE

HA, Glu

McCormick and Pape 1990

transient ICa2+ generates burst at hyperpolarized potentials

normal

TTX(no INa)

- 85 mV - 60 mV

-85 mV

-60 mV

-60 mV

Huguenard & MacCormick, 1994

Rebound Burst Action Potentials Were Absent in the TC Neurons of low-threshold T-type Ca2 KO mice

sites of interaction of different regulatory proteins on Cav subunits

Catteral, 2008

CaV2

regulation of L-type Ca2+ channels by Ca2+ and P

Budde et al., 2002

canales y transportadores de calcio

Hille, 2001

Na+, Ca+2

K+, Cl-

signaling proteinsenzymes

contractionchannel gating

gene expressionsecretion of neurotransmitters

sensorial stimuli

neurotransmitters

othersignaling cascades

voltage-gated channels

ionotropicreceptors: iGluR, GABA

calcium sensors

metabotropicreceptors

other receptors

enzymesgene expression

effects of Ca2+ and calmodulin on neuronal plasticity

Modulation of VG channels

synaptic plasticity

intrinsic plasticity

Synaptic Cams