Inhibition of voltage-gated K+ channel gene expression by the neuropeptide thyrotropin-releasing hormone

Takimoto, Koichi; Gealy, Robert; Fomina, Alla F.; Trimmer, James S.; Levitan, Edwin S.

doi:10.1523/jneurosci.15-01-00449.1995

Cited by 27 publications

(16 citation statements)

References 34 publications

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“…Kv1.5 mRNA and protein have very rapid turnover. 27 Depolarization itself reduces Kv1.5 expression in some cells within 8 hours. 28 The rapid loss of lung Kv1.5 expression temporally parallels the suppression of HPV, which occurs within 2 days of CH.…”

Section: Laboratory Results 2 Weeks After Adenoviral Gene Therapymentioning

confidence: 99%

In Vivo Gene Transfer of the O ₂ -Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats

et al. 2003

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Background-Alveolar hypoxia acutely elicits pulmonary vasoconstriction (HPV). Chronic hypoxia (CH), despiteattenuating HPV, causes pulmonary hypertension (CH-PHT). HPV results, in part, from inhibition of O 2 -sensitive, voltage-gated potassium channels (Kv) in pulmonary artery smooth muscle cells (PASMCs). CH decreases Kv channel current/expression and depolarizes and causes Ca 2ϩ overload in PASMCs. We hypothesize that Kv gene transfer would normalize the pulmonary circulation (restore HPV and reduce CH-PHT), despite ongoing hypoxia. Methods and Results-Adult male Sprague-Dawley rats were exposed to normoxia or CH for 3 to 4 weeks and then nebulized orotracheally with saline or adenovirus (Ad5) carrying genes for the reporter, green fluorescent protein reporterϮhuman Kv1.5 (cloned from normal PA). HPV was assessed in isolated lungs. Hemodynamics, including Fick and thermodilution cardiac output, were measured in vivo 3 and 14 days after gene therapy by use of micromanometer-tipped catheters. Transgene expression, measured by quantitative RT-PCR, was confined to the lung, persisted for 2 to 3 weeks, and did not alter endogenous Kv1.5 levels. Ad5-Kv1.5 caused no mortality or morbidity, except for sporadic, mild elevation of liver transaminases. Ad5-Kv1.5 restored the O 2 -sensitive K ϩ current of PASMCs, normalized HPV, and reduced pulmonary vascular resistance. Pulmonary vascular resistance decreased at day 2 because of increased cardiac output, and remained reduced at day 14, at which time there was concomitant regression of right ventricular hypertrophy and PA medial hypertrophy. Conclusions-Kv1.5 is an important O 2 -sensitive channel and potential therapeutic target in PHT. Kv1.5 gene therapy restores HPV and improves PHT. This is, to the best of our knowledge, the first example of K ϩ channel gene therapy for a vascular disease.

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Section: Laboratory Results 2 Weeks After Adenoviral Gene Therapymentioning

confidence: 99%

In Vivo Gene Transfer of the O ₂ -Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats

et al. 2003

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“…Therefore, variations in the level of I A from cell to cell could explain some of the variation in AP and Ca 2+ oscillation frequency universally observed in unstimulated GH 3 cells. Moreover, TRH changes the level of expression of voltage‐sensitive K + channels in GH 3 cells (Takimoto et al, 1995), which could result in long‐term changes in excitability. Consistent with our results, it has been reported that short‐term exposure to TRH inhibits I A and increases oscillation frequency (Dubinsky and Oxford, 1985).…”

Section: Discussionmentioning

confidence: 99%

Phoneutria nigriventer Toxin Tx3‐1 Blocks A‐Type K⁺ Currents Controlling Ca²⁺ Oscillation Frequency in GH₃ Cells

Kushmerick

Kalapothakis²,

Beirão³

et al. 1999

Journal of Neurochemistry

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GH 3 cells present spontaneous Ca 2ϩ action potentials and oscillations of intracellular Ca 2ϩ , which can be modified by altering the activity of K ϩ or Ca 2ϩ channels. We took advantage of this spontaneous activity to screen for effects of a purified toxin (Tx3-1) from the venom of Phoneutria nigriventer on ion channels. We report that Tx3-1 increases the frequency of Ca 2ϩ oscillations, as do two blockers of potassium channels, 4-aminopyridine and charybdotoxin. Whole-cell patch clamp experiments show that Tx3-1 reversibly inhibits the A-type K ϩ current (I A ) but does not block other K ϩ currents (delayed-rectifying, inward-rectifying, and largeconductance Ca 2ϩ -sensitive) or Ca 2ϩ channels (T and L type) in these cells. In addition, we describe the sequence of a full cDNA clone of Tx3-1, which shows that Tx3-1 has no homology to other known blockers of K ϩ channels and gives insights into the processing of this neurotoxin. We conclude that Tx3-1 is a selective inhibitor of I A , which can be used to probe the role of this channel in the control of cellular function. Based on the effect of Tx3-1, we suggest that I A is an important determinant of the frequency of Ca 2ϩ oscillations in unstimulated GH 3 cells.

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“…The cellular mechanisms by which VSMCs in arterial beds of hypertensive animals select their mem- (46,47,82). Similarly, in the heart, the spontaneous depolarizing activity of atrial myocytes during atrial fibrillation has been linked to the downregulation of K V ␣1.5-subunits (88).…”

Section: What "Signal(s)" Induce Ion Channel Remodeling?mentioning

confidence: 99%

New Expression Profiles of Voltage-gated Ion Channels in Arteries Exposed to High Blood Pressure

Cox¹,

Rusch²

2002

Microcirculation

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The diameters of small arteries and arterioles are tightly regulated by the dynamic interaction between Ca(2+) and K(+) channels in the vascular smooth muscle cells. Calcium influx through voltage-gated Ca(2+) channels induces vasoconstriction, whereas the opening of K(+) channels mediates hyperpolarization, inactivation of voltage-gated Ca(2+) channels, and vasodilation. Three types of voltage-sensitive ion channels have been highly implicated in the regulation of resting vascular tone. These include the L-type Ca(2+) (Ca(L)) channels, voltage-gated K(+) (K(V)) channels, and high-conductance voltage- and Ca(2+)-sensitive K(+) (BK(Ca)) channels. Recently, abnormal expression profiles of these ion channels have been identified as part of the pathogenesis of arterial hypertension and other vasospastic diseases. An increasing number of studies suggest that high blood pressure may trigger cellular signaling cascades that dynamically alter the expression profile of arterial ion channels to further modify vascular tone. This article will briefly review the properties of Ca(L), K(V), and BK(Ca) channels, present evidence that their expression profile is altered during systemic hypertension, and suggest potential mechanisms by which the signal of elevated blood pressure may result in altered ion channel expression. A final section will discuss emerging concepts and opportunities for the development of new vasoactive drugs, which may rely on targeting disease-specific changes in ion channel expression as a mechanism to lower vascular tone during hypertensive diseases.

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Inhibition of voltage-gated K+ channel gene expression by the neuropeptide thyrotropin-releasing hormone

Cited by 27 publications

References 34 publications

In Vivo Gene Transfer of the O ₂ -Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats

In Vivo Gene Transfer of the O ₂ -Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats

Phoneutria nigriventer Toxin Tx3‐1 Blocks A‐Type K⁺ Currents Controlling Ca²⁺ Oscillation Frequency in GH₃ Cells

New Expression Profiles of Voltage-gated Ion Channels in Arteries Exposed to High Blood Pressure

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Inhibition of voltage-gated K+ channel gene expression by the neuropeptide thyrotropin-releasing hormone

Cited by 27 publications

References 34 publications

In Vivo Gene Transfer of the O 2 -Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats

In Vivo Gene Transfer of the O 2 -Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats

Phoneutria nigriventer Toxin Tx3‐1 Blocks A‐Type K+ Currents Controlling Ca2+ Oscillation Frequency in GH3 Cells

New Expression Profiles of Voltage-gated Ion Channels in Arteries Exposed to High Blood Pressure

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In Vivo Gene Transfer of the O ₂ -Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats

In Vivo Gene Transfer of the O ₂ -Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats

Phoneutria nigriventer Toxin Tx3‐1 Blocks A‐Type K⁺ Currents Controlling Ca²⁺ Oscillation Frequency in GH₃ Cells