scholarly journals Tissue-specific adrenergic regulation of the L-type Ca2+ channel CaV1.2

2020 ◽  
Vol 13 (663) ◽  
pp. eabc6438
Author(s):  
Kwun Nok Mimi Man ◽  
Peter Bartels ◽  
Mary C. Horne ◽  
Johannes W. Hell
Keyword(s):  
Smooth Muscle ◽  
Stress Response ◽  
Protein Kinase ◽  
Adrenergic Receptors ◽  
Camp Production ◽  
Adrenergic Regulation ◽  
Cardiomyocyte Contractility ◽  
Fight Or Flight Response ◽  
Β Adrenergic Receptors ◽  
Kinase A

Ca2+ influx through the L-type Ca2+ channel Cav1.2 triggers each heartbeat. The fight-or-flight response induces the release of the stress response hormone norepinephrine to stimulate β-adrenergic receptors, cAMP production, and protein kinase A activity to augment Ca2+ influx through Cav1.2 and, consequently, cardiomyocyte contractility. Emerging evidence shows that Cav1.2 is regulated by different mechanisms in cardiomyocytes compared to neurons and vascular smooth muscle cells.

scholarly journals Reconstitution of β-adrenergic regulation of CaV1.2: Rad-dependent and Rad-independent protein kinase A mechanisms

2021 ◽  
Vol 118 (21) ◽  
pp. e2100021118
Author(s):  
Moshe Katz ◽  
Suraj Subramaniam ◽  
Orna Chomsky-Hecht ◽  
Vladimir Tsemakhovich ◽  
Veit Flockerzi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Adrenergic Receptors ◽  
Calcium Influx ◽  
Inhibitory Protein ◽  
Reconstituted System ◽  
Distinct Features ◽  
Β Adrenergic Receptors ◽  
Independent Protein ◽  
Kinase A

L-type voltage-gated CaV1.2 channels crucially regulate cardiac muscle contraction. Activation of β-adrenergic receptors (β-AR) augments contraction via protein kinase A (PKA)–induced increase of calcium influx through CaV1.2 channels. To date, the full β-AR cascade has never been heterologously reconstituted. A recent study identified Rad, a CaV1.2 inhibitory protein, as essential for PKA regulation of CaV1.2. We corroborated this finding and reconstituted the complete pathway with agonist activation of β1-AR or β2-AR in Xenopus oocytes. We found, and distinguished between, two distinct pathways of PKA modulation of CaV1.2: Rad dependent (∼80% of total) and Rad independent. The reconstituted system reproduces the known features of β-AR regulation in cardiomyocytes and reveals several aspects: the differential regulation of posttranslationally modified CaV1.2 variants and the distinct features of β1-AR versus β2-AR activity. This system allows for the addressing of central unresolved issues in the β-AR–CaV1.2 cascade and will facilitate the development of therapies for catecholamine-induced cardiac pathologies.

scholarly journals β-Agonist-mediated Relaxation of Airway Smooth Muscle Is Protein Kinase A-dependent

2014 ◽  
Vol 289 (33) ◽  
pp. 23065-23074 ◽  
Author(s):  
Sarah J. Morgan ◽  
Deepak A. Deshpande ◽  
Brian C. Tiegs ◽  
Anna M. Misior ◽  
Huandong Yan ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Airway Smooth Muscle ◽  
Kinase A

Mesovarial Leiomyomas in Rats in a Chronic Toxicity Study of Soterenol Hydrochloride

1971 ◽  
Vol 8 (5-6) ◽  
pp. 452-457 ◽  
Author(s):  
L. W. Nelson ◽  
W. A. Kelly
Keyword(s):  
Smooth Muscle ◽  
Adrenergic Receptors ◽  
Dose Group ◽  
Chronic Toxicity ◽  
Low Dose ◽  
Toxicity Study ◽  
Ovarian Cysts ◽  
High Dose ◽  
Oral Toxicity ◽  
Β Adrenergic Receptors

In an 18-month oral toxicity study of soterenol hydrochloride, a stimulant of the β-adrenergic receptors, mesovarial leiomyomas were observed in three of 30 low-dose, six of 30 middle-dose and 10 of 30 high-dose rats. There was also an increase in the prevalence of ovarian cysts and of focal hyperplasia of smooth muscle in the mesovaria in the treated rats, especially in the high-dose group.

Interplay of VIP and nitric oxide in regulation of the descending relaxation phase of peristalsis

1993 ◽  
Vol 264 (2) ◽  
pp. G334-G340 ◽  
Author(s):  
J. R. Grider
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Protein Kinase ◽  
Protein Kinase G ◽  
Rat Colon ◽  
No Production ◽  
Field Stimulation ◽  
Relaxant Effect ◽  
Relaxation Phase ◽  
Kinase A

Involvement of vasoactive intestinal peptide (VIP) and nitric oxide (NO) in neurally induced relaxation was examined in smooth muscle from rat colon. Relaxation induced by field stimulation or radial stretch (i.e., descending relaxation phase of the peristaltic reflex) was accompanied by VIP release and NO production. NG-nitro-L-arginine (L-NNA) abolished NO production in both preparations but only partly inhibited VIP release (45 +/- 8% at 8 Hz and 59 +/- 10% at 10 g stretch) and relaxation (62 +/- 5% and 35 +/- 6%); the effect of L-NNA was reversed by L-arginine but not D-arginine. The pattern implied that NO production normally acts to enhance VIP release. In addition, VIP induced relaxation and stimulated NO production in muscle strips and isolated colonic muscle cells: L-NNA abolished NO production but only partly inhibited relaxation (58 +/- 6%); oxyhemoglobin had no effect. The effect of L-NNA on relaxation was reversed by L-arginine but not by D-arginine. The protein kinase A inhibitor (R)-p-adenosine 3',5'-cyclic phosphorothioate [(R)-p-cAMPS] and the protein kinase G inhibitor KT5823 inhibited VIP-induced relaxation by 76 +/- 5 and 35 +/- 4%, respectively; a combination of the two inhibitors abolished relaxation. (R)-p-cAMPS blocked the direct relaxant effect of VIP, whereas KT5823 blocked the indirect effect of VIP mediated by NO.(ABSTRACT TRUNCATED AT 250 WORDS)

Protein kinase A mediates activation of ATP-sensitive K+ currents by CGRP in gallbladder smooth muscle

1994 ◽  
Vol 267 (3) ◽  
pp. G494-G499 ◽  
Author(s):  
L. Zhang ◽  
A. D. Bonev ◽  
G. M. Mawe ◽  
M. T. Nelson
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Whole Cell Patch Clamp ◽  
Camp Analogue ◽  
Calcitonin Gene ◽  
Transduction Mechanisms ◽  
Spontaneous Action ◽  
Spontaneous Action Potentials ◽  
Kinase A

The signal transduction mechanisms underlying the activation of ATP-sensitive potassium (KATP) current by calcitonin gene-related peptide (CGRP) in gallbladder smooth muscle were examined with intracellular microelectrode recording and whole cell patch-clamp techniques. In the intact gallbladder preparation, the adenylyl cyclase activator forskolin hyperpolarized the membrane potential and abolished spontaneous action potentials. This response was inhibited by the KATP channel blocker glibenclamide. CGRP (10 nM), forskolin (10 microM), the membrane-permeable adenosine 3',5'-cyclic monophosphate (cAMP) analogue adenosine 3',5'-cyclic monophosphothioate (Sp-cAMP[S]; 500 microM), and the catalytic subunit of protein kinase A (100 U/ml) activated glibenclamide-sensitive currents in enzymatically dissociated gallbladder smooth muscle cells. CGRP activation of potassium currents was prevented by dialysis of the cell cytoplasm with guanosine 5'-O-(2-thiodiphosphate) (5 mM) or a specific peptide inhibitor of protein kinase A (2.3 microM). Okadaic acid (5 microM), a phosphatase inhibitor, slowed the deactivation of the KATP current, following removal of CGRP. The results of this study indicate that CGRP hyperpolarizes gallbladder smooth muscle by elevation of cAMP and subsequent stimulation of protein kinase A.

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