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Molecular and pharmacological characteristics of the gerbil ?(1a)-adrenergic receptor.

ABSTRACT: The spiral modiolar artery supplies blood and essential nutrients to the cochlea. Our previous functional study indicates the ?(1A)-adrenergic receptor subtype mediates vasoconstriction of the gerbil spiral modiolar artery. Although the gerbil cochlea is often used as a model in hearing research, the molecular and pharmacological characteristics of the cloned gerbil ?(1a)-adrenergic receptor have not been determined. Thus we cloned, expressed and characterized the gerbil ?(1a)-adrenergic receptor and then compared its molecular and pharmacological properties to those of other mammalian ?(1a)-adrenergic receptors. The cDNA clone contained 1404 nucleotides, which encoded a 467 amino acid peptide with a deduced sequence having 96.8, 96.4 and 91.6% identity to rat, mouse and human ?(1a)-receptors, respectively. We transiently transfected the ?(1a)-adrenergic receptor into COS-1 cells and determined its pharmacological characteristics by [(3)H]prazosin binding. Unlabeled prazosin had a K(i) of 0.89±0.1nM. The ?(1A)-adrenergic receptor-selective antagonists, 5-methylurapidil and WB-4101, bound with high affinity and had K(i) values of 4.9±1 and 1.0±0.1nM, respectively. BMY-7378, an ?(1D)-adrenergic receptor-selective antagonist, bound with low affinity (260±60nM). The 91.6% amino acid sequence identity and K(i)s of the cloned gerbil ?(1a)-adrenergic receptor are similar to those of the human ?(1a)-adrenergic receptor clone. These results show that the gerbil ?(1a)-adrenergic receptor is representative of the human ?(1a)-adrenergic receptor, lending validity to the use of the gerbil spiral modiolar artery as a model in studies of vascular disorders of the cochlea.

SUBMITTER: Witt KM

PROVIDER: S-EPMC4030439 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Molecular and pharmacological characteristics of the gerbil α(1a)-adrenergic receptor.

Witt Kelly M KM Bockman Charles S CS Dang Herbert K HK Gruber Daniel D DD Wangemann Philine P Scofield Margaret A MA

Hearing research 20111110 1-2

The spiral modiolar artery supplies blood and essential nutrients to the cochlea. Our previous functional study indicates the α(1A)-adrenergic receptor subtype mediates vasoconstriction of the gerbil spiral modiolar artery. Although the gerbil cochlea is often used as a model in hearing research, the molecular and pharmacological characteristics of the cloned gerbil α(1a)-adrenergic receptor have not been determined. Thus we cloned, expressed and characterized the gerbil α(1a)-adrenergic recepto ...[more]

PMID: 22101021

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Project description:AimsTo determine the mechanisms by which the ?1A-adrenergic receptor (AR) regulates cardiac contractility.BackgroundWe reported previously that transgenic mice with cardiac-restricted ?1A-AR overexpression (?1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this G?q/11-coupled receptor in hypertrophy.MethodsContractility, calcium (Ca(2+)) kinetics and sensitivity, and contractile proteins were examined in cardiomyocytes, isolated hearts and skinned fibers from ?1A-TG mice (170-fold overexpression) and their non-TG littermates (NTL) before and after ?1A-AR agonist stimulation and blockade, angiotensin II (AngII), and Rho kinase (ROCK) inhibition.ResultsHypercontractility without hypertrophy with ?1A-AR overexpression is shown to result from increased intracellular Ca(2+) release in response to agonist, augmenting the systolic amplitude of the intracellular Ca(2+) concentration [Ca(2+)]i transient without changing resting [Ca(2+)]i. In the absence of agonist, however, ?1A-AR overexpression reduced contractility despite unchanged [Ca(2+)]i. This hypocontractility is not due to heterologous desensitization: the contractile response to AngII, acting via its G?q/11-coupled receptor, was unaltered. Rather, the hypocontractility is a pleiotropic signaling effect of the ?1A-AR in the absence of agonist, inhibiting RhoA/ROCK activity, resulting in hypophosphorylation of both myosin phosphatase targeting subunit 1 (MYPT1) and cardiac myosin light chain 2 (cMLC2), reducing the Ca(2+) sensitivity of the contractile machinery: all these effects were rapidly reversed by selective ?1A-AR blockade. Critically, ROCK inhibition in normal hearts of NTLs without ?1A-AR overexpression caused hypophosphorylation of both MYPT1 and cMLC2, and rapidly reduced basal contractility.ConclusionsWe report for the first time pleiotropic ?1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.

Dataset Information

Molecular and pharmacological characteristics of the gerbil ?(1a)-adrenergic receptor.

Publications

Molecular and pharmacological characteristics of the gerbil α(1a)-adrenergic receptor.

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