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