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Membrane lipid modulations remove divalent open channel block from TRP-like and NMDA channels.

ABSTRACT: Open channel block is a process in which ions bound to the inside of a channel pore block the flow of ions through that channel. Repulsion of the blocking ions by depolarization is a known mechanism of open channel block removal. For the NMDA channel, this mechanism is necessary for channel activation and is involved in neuronal plasticity. Several types of transient receptor potential (TRP) channels, including the Drosophila TRP and TRP-like (TRPL) channels, also exhibit open channel block. Therefore, removal of open channel block is necessary for the production of the physiological response to light. Because there is no membrane depolarization before the light response develops, it is not clear how the open channel block is removed, an essential step for the production of a robust light response under physiological conditions. Here we present a novel mechanism to alleviate open channel block in the absence of depolarization by membrane lipid modulations. The results of this study show open channel block removal by membrane lipid modulations in both TRPL and NMDA channels of the photoreceptor cells and CA1 hippocampal neurons, respectively. Removal of open channel block is characterized by an increase in the passage-rate of the blocking cations through the channel pore. We propose that the profound effect of membrane lipid modulations on open channel block alleviation, allows the productions of a robust current in response to light in the absence of depolarization.

SUBMITTER: Parnas M

PROVIDER: S-EPMC2672305 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and purposePre-synaptic neurotransmitter release is largely dependent on Ca(2+) entry through P/Q-type (Ca(V)2.1) voltage-gated Ca(2+) channels (PQCCs) at most mammalian, central, fast synapses. Barbiturates are clinical depressants and inhibit pre-synaptic Ca(2+) entry. PQCC barbiturate pharmacology is generally unclear, specifically in man. The pharmacology of the barbiturate pentobarbital (PB) in human recombinant alpha(1A) PQCCs has been characterized.Experimental approachPB effects on macroscopic Ca(2+)(I(Ca)) and Ba(2+)(I(Ba)) currents were studied using whole-cell patch clamp recording in HEK-293 cells heterologously expressing (alpha(1A))(human)(beta(2a)alpha(2)delta-1)(rabbit) PQCCs.Key resultsPB reversibly depressed peak current (I(peak)) and enhanced apparent inactivation (fractional current at 800 ms, r(800)) in a concentration-dependent fashion irrespective of charge carrier (50% inhibitory concentration: I(peak), 656 microM; r(800), 104 microM). Rate of mono-exponential I(Ba) decay was linearly dependent on PB concentration. PB reduced channel availability by deepening non-steady-state inactivation curves without altering voltage dependence, slowed recovery from activity-induced unavailable states and produced use-dependent block. PB (100 microM) induced use-dependent block during physiological, high frequency pulse trains and overall depressed PQCC activity by two-fold.Conclusion and implicationsThe results support a PB pharmacological mechanism involving a modulated receptor with preferential slow, bimolecular, open channel block (K(d)= 15 microM). Clinical PB concentrations (<200 microM) inhibit PQCC during high frequency activation that reduces computed neurotransmitter release by 16-fold and is comparable to the magnitude of Ca(2+)-dependent facilitation, G-protein modulation and intrinsic inactivation that play critical roles in PQCC modulation underlying synaptic plasticity. The results are consistent with the hypothesis that PB inhibition of PQCCs contributes to central nervous system depression underlying anticonvulsant therapy and general anaesthesia.

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Membrane lipid modulations remove divalent open channel block from TRP-like and NMDA channels.

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