Molecular Insights into Regulation of L-Type Ca Channel Function

Lory, Philippe; Váradi, Gyula; Schwartz, Austin B.

doi:10.1152/physiologyonline.1991.6.6.277

Cited by 9 publications

(11 citation statements)

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“…In terms of inactivation kinetics (non-inactivating Z,,), Z,, is similar to the fast rising non-inactivating DHP Ca" channel reported in dysgenic skeletal muscle [26]. Recently, molecular biological studies have revealed that the HVA Ca" channel is a protein complex containing a,, a,/S, /3 and y subunits [27,28]. Recent studies have revealed a diversity among L-type Ca2' channels arising from: (i) multiples genes encoding the pore forming a,-subunit; and (ii) various genes (at least 4) encoding the auxilliary B-subunit.…”

supporting

confidence: 66%

Endogenous DHP‐sensitive Ca²⁺ channels in Pleurodeles oocytes

Ouadid¹,

Browaeys-Poly

Vilain

et al. 1994

FEBS Letters

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The double electrode voltage-clamp technique was used to study voltage-dependent Ca*' channels in Pleurodeles oocytes. From a holding potential of -80 mV, Ba-current (ZBa) (recorded in Cl-free solution, Ba 2+ = 40 mM) activated at -36.7 + 4 mV, peaked at -11.6 f 4 mV and reversed at 55 + 7 mV (n = 24). This current activated slowly (rise time was 0.98 f 0.2 s; n = 14 at -10 mV) and was not inactivated. Cadmium (Cd", 5OOpM) completely inhibited I,,. The effect of Cd2+ was dose-dependent (ECSo = 37 + 5pM; n = 5). Moreover, ZBa was insensitive to w-conotoxin (10pM) but interestingly this ZBa displayed dihydropyridine (DHP) sensitivity. Bay K 8644 (SpM), a DHP activator, increased the peak current amplitude in a dose-dependent manner (EC,,, = 5.9 f 0.6 PM; n = 10) and shifted the threshold and the maximum of current/voltage relationship towards negative potentials by -10 mV. Nifedipine (5 PM), a DHP antagonist, decreased Z,, by 80% at HP of -80 mV (EC,, = 1.2 + 0.2 PM; n = 6). We concluded that Pleurodeles oocytes possess High-Voltage Activated Ca" channels with properties similar to L-type Ca" channels.

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supporting

confidence: 66%

Endogenous DHP‐sensitive Ca²⁺ channels in Pleurodeles oocytes

Ouadid¹,

Browaeys-Poly

Vilain

et al. 1994

FEBS Letters

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“…43,44 Thus, all 3 pharmacological Ca 2ϩ channel blockers share the unique property of inhibiting L-type channels by binding to a voltage-sensitive portion of the ␣ 1 subunit. 31,45,46 As a consequence, phenylalkylamines, benzothiazepines, and dihydropyridines either are inactive 32 or have a small inhibitory effect at negative potentials (Ϫ80 mV), as reported for a dihydropyridine in the rabbit ear artery, 47 and are unable to induce a significant "initial" channel block. Therefore, the high efficacy of the farnesol block at negative membrane potentials (Ϫ80 mV), ie, without the need for prior channel opening or inactivation, suggests the possibility of a different binding site on the Ca2ϩ channel, perhaps at a point less affected by membrane potential than the ones recognized by currently known Ca 2ϩ channel blockers.…”

Section: Discussionmentioning

confidence: 88%

Farnesol Blocks the L-Type Ca ²⁺ Channel by Targeting the α _1C Subunit

Luft

Bychkov

Gollasch

et al. 1999

ATVB

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Abstract-We recently demonstrated that farnesol, a 15-carbon isoprenoid, blocks L-type Ca 2ϩ channels in vascular smooth muscle cells. To elucidate farnesolЈs mechanism of action, we performed whole-cell and perforated-patch clamp experiments in rat aortic A7r5 cells and in Chinese hamster ovary (CHO) C9 cells expressing smooth muscle Ca 2ϩ channel ␣ 1C subunits. Farnesol dose-dependently and voltage-independently inhibited Ba 2ϩ currents in both A7r5 and CHOC9 cells, with similar half-maximal inhibitions at 2.6 and 4.3 mmol/L, respectively (PϭNS). In both cell lines, current inhibition by farnesol was prominent over the whole voltage range without changes in the current-voltage relationship peaks. Neither intracellular infusion of the stable GDP analogue guanosine-5Ј-O-(2-thiodiphosphate) (100 mmol/L) via the patch pipette nor strong conditioning membrane depolarization prevented the inhibitory effect of farnesol, which indicates G protein-independent inhibition of Ca 2ϩ channels. In an analysis of the steady-state inactivation curve for voltage dependence, farnesol induced a significant, negative shift (Ϸ10 mV) of the potential causing 50% channel inactivation in both cell lines (PϽ0.001). In contrast, the steepness factor characterizing the voltage sensitivity of the channels was unaffected. Unlike pharmacological Ca 2ϩ channel blockers, farnesol blocked Ca 2ϩ currents in the resting state: initial block was 63Ϯ8% in A7r5 cells and 50Ϯ9% in CHOC9 cells at a holding potential of Ϫ80 mV. We then gave 500 mg/kg body weight farnesol by gavage to Sabra hypertensive and normotensive rats and found that farnesol reduced blood pressure significantly in the hypertensive strain for at least 48 hours. We conclude that farnesol may represent an endogenous smooth muscle L-type Ca 2ϩ channel antagonist. Because farnesol is active in cells expressing only the pore-forming ␣ 1 subunit, the data further suggest that this subunit represents the molecular target for farnesol binding and principal action. Key Words: smooth muscle cells Ⅲ farnesol Ⅲ patch clamp Ⅲ calcium channel blockers Ⅲ L-class channels F arnesol is 1 of several nonsterol mevalonate derivatives in the cholesterol pathway. 1 Farnesol is derived from farnesyl pyrophosphate, a C 15 isoprenoid lipid implicated in the regulation of G protein activity. 2 Some studies suggest that farnesol participates in the control of cholesterol synthesis by increasing 3-hydroxy-3-methylglutaryl coenzyme A reductase degradation. 3,4 Others suggest that farnesol is implicated in the regulation of cell growth. 5 Roullet et al 6 recently showed that farnesol inhibited contraction in both human and animal arteries. This effect explained earlier reports of a mevalonate-dependent positive regulation of vascular tone. 7,8 These studies featured a series of experiments that showed that farnesol blunted the KCl-induced increase in intracellular Ca 2ϩ concentration in intact arteries and vascular smooth muscle cells (VSMCs) in culture. 9 The patch-clamp technique revealed that micromolar co...

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“…pore-forming ␣1-subunits responsible for the L-type current: ␣1S mainly present in skeletal muscle (Tanabe et al, 1987); ␣1C found in cardiac muscle, smooth muscle (Lory et al, 1991), and neurons (Hell et al, 1993); ␣1D predominantly found in neurosecretory cells (Chin et al, 1992) but also in neurons, cardiac myocytes, and differentiated NG108-15 cells (Hell et al, 1993;Kamp et al, 1995;Wyatt et al, 1997); and a recently described retina-specific ␣1F (Strom et al, 1998). Selectivity with respect to the L-type ICa was reported for the calcium channel antagonists (Hockerman et al, 1997;Striessnig et al, 1998).…”

Section: Sarco-endoplasmic Atpase Blocker Inhibits Ca 2؉ Currentsmentioning

confidence: 95%

Sarco-Endoplasmic ATPase Blocker 2,5-Di(tert-butyl)-1,4-benzohydroquinone Inhibits N-, P-, and Q- but Not T-, L-, or R-Type Calcium Currents in Central and Peripheral Neurons

Scamps¹,

Vigues²,

Restituito³

et al. 2000

Mol Pharmacol

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The effects of 2,5-di(tert-butyl)-1,4-benzohydroquinone (tBHQ), a synthetic phenolic antioxidant and a blocker of the sarcoendoplasmic ATPase, were evaluated on low and high voltageactivated Ca 2ϩ currents (ICas) with rodent dorsal root ganglion, hippocampal, and motor neurons. In all cell types tested, tBHQ (IC 50 ϭ 35 M) blocked ICa at concentrations used to inhibit sarco-endoplasmic ATPase. This effect was specific to tBHQ because the other sarco-endoplasmic reticulum calcium ATPase pump inhibitors (thapsigargin and cyclopiazonic acid) had no effect. Selective blockade of the N-type current with -conotoxin GVIA and of P-(motoneuron) or Q-type currents (hippocampal neuron) with -agatoxin IVA indicated that tBHQ inhibited N, P, and Q types of ICa. tBHQ had no effect on nitrendipine-sensitive (L-type) and residual drug-resistant (Rtype) ICa, nor on the low voltage-activated T-type ICa. Contrary to neuronal cells, the L-type ICa was inhibited by tBHQ in a differentiated mouse neuroblastoma and rat glioma hybrid cell line. Injection of cDNAs encoding the ␣1A, ␣1B, ␣1C, and ␣1E subunits into oocytes showed that tBHQ blocked ICas at the level of the pore-forming protein. This effect of tBHQ on ICa should be considered when interpreting results obtained with tBHQ used on neuronal preparations. It also may be useful for developing new strategies for the generation of more potent intracellular calcium transient inhibitors.Plasmalemmal voltage-gated calcium channels (VGCCs) initiate intracellular calcium transients and control many aspects of neuronal processes, including the generation of calcium-dependent action potentials, neurotransmitter release, regulation of neuronal death, synapse formation and elimination, phenotypic differentiation, and gene expression (Ghosh and Greenberg, 1995;Gu and Spitzer, 1997). These channels are activated by membrane depolarization, leading to a transmembrane calcium influx and a transient increase in cytoplasmic free calcium concentration. It has become clear, however, that these voltage-dependent calcium transients also are generated by mechanisms involving the release of calcium from intracellular stores in the sarco-endoplasmic reticulum. In neurons, at least two types of calcium stores have been identified in the sarco-endoplasmic reticulum, based on calcium-release channels: caffeine-ryanodinesensitive and inositol-1,3,4-triphosphate-sensitive calcium channels. The relationships among voltage-activated calcium influx, release of calcium from cytoplasmic stores, and intracellular calcium transients are complex and are only just beginning to be understood.Five VGCC subtypes (T, L, N, P/Q, and R) were initially defined according to electrophysiological and pharmacological characteristics (Birnbaumer et al., 1994) and, more recently, these definitions have been extended to take into account amino acid sequences (Perez-Reyes and Schneider, 1994;Perez-Reyes et al., 1998). Similarly, at least three intracellular calcium channel subtypes have been characterized at the molecular l...

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Molecular Insights into Regulation of L-Type Ca Channel Function

Cited by 9 publications

References 0 publications

Endogenous DHP‐sensitive Ca²⁺ channels in Pleurodeles oocytes

Endogenous DHP‐sensitive Ca²⁺ channels in Pleurodeles oocytes

Farnesol Blocks the L-Type Ca ²⁺ Channel by Targeting the α _1C Subunit

Sarco-Endoplasmic ATPase Blocker 2,5-Di(tert-butyl)-1,4-benzohydroquinone Inhibits N-, P-, and Q- but Not T-, L-, or R-Type Calcium Currents in Central and Peripheral Neurons

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Molecular Insights into Regulation of L-Type Ca Channel Function

Cited by 9 publications

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Endogenous DHP‐sensitive Ca2+ channels in Pleurodeles oocytes

Endogenous DHP‐sensitive Ca2+ channels in Pleurodeles oocytes

Farnesol Blocks the L-Type Ca 2+ Channel by Targeting the α 1C Subunit

Sarco-Endoplasmic ATPase Blocker 2,5-Di(tert-butyl)-1,4-benzohydroquinone Inhibits N-, P-, and Q- but Not T-, L-, or R-Type Calcium Currents in Central and Peripheral Neurons

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Endogenous DHP‐sensitive Ca²⁺ channels in Pleurodeles oocytes

Endogenous DHP‐sensitive Ca²⁺ channels in Pleurodeles oocytes

Farnesol Blocks the L-Type Ca ²⁺ Channel by Targeting the α _1C Subunit