Diverse regulation of IP₃ and ryanodine receptors by pentazocine through σ₁-receptor in cardiomyocytes

Abstract

Although pentazocine binds to σ1-receptor (σ1R) with high affinity, the physiological relevance of its binding remains unclear. We first confirmed that σ1R stimulation with pentazocine rescues contractile dysfunction following pressure overload (PO)-induced cardiac hypertrophy ovariectomized (OVX) female rats. In in vivo studies, vehicle, pentazocine (0.5-1.0 mg/kg ip), and NE-100 (1.0 mg/kg po), a σ1R antagonist, were administered for 4 wk (once daily) starting from the onset of aortic banding after OVX. We also examined antihypertrophic effects of pentazocine (0.5-1 μM) in cultured cardiomyocytes exposed to angiotensin II. Pentazocine administration significantly inhibited PO-induced cardiac hypertrophy and rescued hypertrophy-induced impairment of cardiac dysfunctions such as left ventricular end-diastolic pressure, left ventricular developed pressure, and left ventricular contraction and relaxation (±dp/dt) rates. Coadministration of NE-100 with pentazocine eliminated pentazocine-induced amelioration of heart dysfunction. Interestingly, pentazocine administration inhibited PO-induced σ1R reduction and inositol-1,4,5-trisphosphate (IP3) receptor type 2 (IP3R2) upregulation in heart. Therefore, the reduced mitochondrial ATP production following PO was restored by pentazocine administration. Furthermore, we found that σ1R binds to the ryanodine receptor (RyR) in addition to IP3 receptor (IP3R) in cardiomyocytes. The σ1R/RyR complexes were decreased following OVX-PO and restored by pentazocine administration. We noticed that pentazocine inhibits the ryanodine-induced Ca(2+) release from sarcoplasmic reticulum (SR) in cultured cardiomyocytes. Taken together, the stimulation of σ1R by pentazocine rescues cardiac dysfunction by restoring IP3R-mediated mitochondrial ATP production and by suppressing RyR-mediated Ca(2+) leak from SR in cardiomyocytes.

Partners in Crime: Towards New Ways of Targeting Calcium Channels

“…There, the Sig-1R stabilizes IP3-activated IP3R preventing its degradation and allowing sustained calcium efflux towards the mitochondria to increase ATP production and maintain cell survival [49]. The chaperoning of IP3R by Sig-1R was shown to protect cells against stress in neurons [134][135][136][137][138] as well as cardiomyocytes [139,140]. Alteration of this mechanism has been linked with neurological disorders such as Huntington's disease [141], amyotrophic lateral sclerosis (ALS) [142,143], and cancer [144,145].…”

“…The Sig-1R is targeted by many drugs that can be used to modulate IP3R calcium signaling. Indeed, the IP3R modulation by Sig-1R was shown to be reinforced by Sig-1R agonists and inhibited by antagonists in many different physiological and pathological cellular contexts [134][135][136][137][138][139][140][141]144,145]. Conversely, the Sig-1R can also modulate IP3R indirectly by stimulating IP3 production [148][149][150], increasing IP3R expression [151] and also by increasing Bcl-2 expression [152][153][154].…”

Oxidative stress involving changes in Nrf2 and ER stress in early stages of Alzheimer's disease

“…In fact, ROS production by peripheral cells 724 was shown to be inhibited by antipsychotic drugs such as risperidone 725 [14] or anti-cholesterol drugs, namely statins [86,87]. ER stress was 726 also shown to be affected by antipsychotic compounds [83]. Important- …”

Potential Molecular Mechanisms on the Role of the Sigma-1 Receptor in the Action of Cocaine and Methamphetamine

“…In the heart, IP3R2 contributes to the Ca 2+ influx into mitochondria and the Sig1R is physically associated with IP3R2. Interestingly, the Sig-1R stimulation by the agonists ameliorates cardiac hypertrophy and dysfunction through the enhancement of the Sig-1R-IP3R2 interaction and by restoring the IP3R2-mediated Ca 2+ mobilization from the ER into the mitochondria and the resultant mitochondrial ATP production [97, 98]. Recently, it was suggested that the RyR is involved in the cardiac protective effects of Sig-1R agonists [98, 99].…”

“…Interestingly, the Sig-1R stimulation by the agonists ameliorates cardiac hypertrophy and dysfunction through the enhancement of the Sig-1R-IP3R2 interaction and by restoring the IP3R2-mediated Ca 2+ mobilization from the ER into the mitochondria and the resultant mitochondrial ATP production [97, 98]. Recently, it was suggested that the RyR is involved in the cardiac protective effects of Sig-1R agonists [98, 99]. Therefore, the Sig-1R may regulate a variety of intracellular Ca 2+ channels operated through both IP3Rs and RyRs, depending on the types of cells as well as the expression patterns of IP3R and RyR isoforms.…”