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. 2008 Oct;26(10):1966-75.
doi: 10.1097/HJH.0b013e328309eff9.

Transient receptor potential vanilloid subtype 1 channel mediated neuropeptide secretion and depressor effects: role of endoplasmic reticulum associated Ca2+ release receptors in rat dorsal root ganglion neurons

Wei Huang  1 , Hui Wang, James J Galligan, Donna H Wang
Affiliations

Transient receptor potential vanilloid subtype 1 channel mediated neuropeptide secretion and depressor effects: role of endoplasmic reticulum associated Ca2+ release receptors in rat dorsal root ganglion neurons

Wei Huang et al. J Hypertens. 2008 Oct.

Abstract

Objective: This study tests the hypothesis that the transient receptor potential vanilloid subtype 1 channel induced neuropeptide secretion and depressor response are mediated by, at least in part, activation of endoplasmic reticulum associated Ca release receptors, leading to increased cytosolic Ca in dorsal root ganglion neurons.

Methods/results: Bolus injection of capsaicin (10 or 50 microg/kg), a selective transient receptor potential vanilloid subtype 1 channel agonist, into anesthetized male Wistar rats caused a dose-dependent decrease in mean arterial pressure (P < 0.05). Capsaicin (50 microg/kg)-induced depressor effects and increase in plasma calcitonin gene related peptide (CGRP) levels (-29 +/- 2 mmHg, 82.2 +/- 5.0 pg/ml) were abolished by a selective transient receptor potential vanilloid subtype 1 channel antagonist, capsazepine (3 mg/kg, -4 +/- 1 mmHg, 41.8 +/- 4.4 pg/ml, P < 0.01), and attenuated by a selective ryanodine receptor antagonist, dantrolene (5 mg/kg, -12 +/- 1 mmHg, 57.2 +/- 2.6 pg/ml, P < 0.01), but unaffected by an inhibitor of endoplasmic reticulum Ca-ATPase, thapsigargin (50 microg/kg, -30 +/- 1 mmHg, 73.8 +/- 2.3 pg/ml, P > 0.05), or an antagonist of the inositol (1,4,5)-trisphosphate receptor, 2-aminoethoxydiphenyl borate (3 mg/kg, -34 +/- 5 mmHg, 69.0 +/- 3.7 pg/ml, P > 0.05). CGRP8-37 (1 mg/kg), a selective CGRP receptor antagonist, also blocked capsaicin-induced depressor effects. In contrast, dantrolene had no effect on CGRP (1 microg/kg)-induced depressor effects. In vitro, capsaicin (0.3 micromol/l) increased intracellular Ca concentrations and CGRP release from freshly isolated sensory neurons in dorsal root ganglion (P < 0.01), which were blocked by capsazepine (10 micromol/l) and attenuated by dantrolene but not thapsigargin or 2-aminoethoxydiphenyl borate.

Conclusion: Our results indicate that transient receptor potential vanilloid subtype 1 channel activation triggers ryanodine receptor but not inositol (1,4,5)-trisphosphate receptor dependent Ca release from endoplasmic reticulum in dorsal root ganglion neurons, leading to increased CGRP release and consequent depressor effects.

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Figures

Figure 1
Figure 1
A, Time-dependent responses of MAP to bolus injection of vehicle or CAP (10 μg/kg; 50 μg/kg). B, Changes in MAP 70 seconds after bolus injection of vehicle or CAP (10 μg/kg; 50 μg/kg). Values are mean±SE (the same for all data presented below; n = 6 to 7). *P<0.05 compared to corresponding vehicles. †P<0.05 compared to rats treated with CAP (10 μg/kg).
Figure 2
Figure 2
A, Time-dependent responses of heart rate to bolus injection of vehicle or CAP (10 μg/kg; 50 μg/kg). B, Changes in heart rate 70 seconds after bolus injection of vehicle or CAP (10 μg/kg; 50 μg/kg). n = 6 to 7. *P<0.05 compared to corresponding vehicles. †P<0.05 compared to rats treated with CAP (10 μg/kg).
Figure 3
Figure 3
A, Effects of pretreatment with CAPZ (3 mg/kg) or CGRP8-37 (1 mg/kg/min × 2 minutes followed by 0.5 mg/kg/min × 4 minutes) on CAP (50 μg/kg)-induced changes in MAP. B, Effects of pretreatment with dantrolene (5 mg/kg), TG (50 μg/kg) or 2-APB (3 mg/kg) on CAP (50 μg/kg)-induced changes in MAP. n = 6 to 7. * P<0.05 compared to corresponding vehicles. †P<0.01 compared to rats treated with CAP alone. #P<0.01 compared to rats treated with dantrolene+CAP.
Figure 4
Figure 4
Effects of pretreatment with dantrolene (5 mg/kg) on CGRP (1 μg/kg)—induced changes in MAP. B, Changes in MAP 60 seconds after injection of vehicle or CGRP (1 μg/kg) with or without dantrolene. n = 6 to 7. *P<0.05 compared to corresponding vehicles.
Figure 5
Figure 5
Time-dependent responses of mean arterial pressure (MAP, A) or heart rate (HR, B) to bolus injection of vehicle or CAP (50 μg/kg) in baroreceptor denervated rats. n = 6 to 7. *P<0.05 compared to corresponding vehicles.
Figure 6
Figure 6
A, Immunoactive CGRP levels in plasma of rats treated with vehicle, CAP (10 μg/kg; 50 μg/kg). B. Effects of pretreatment with CAPZ (3 mg/kg), dantrolene (5 mg/kg), TG (50 μg/kg), or 2-APB (3 mg/kg) on CAP (50 μg/kg)-induced CGRP release in plasma. n = 6 to 7. *P<0.05 compared to corresponding vehicles. †P<0.01 compared to rats treated with CAP (10 μg /kg) in panel A or CAP (50 μg/kg) alone in panel B. #P<0.05 compared to rats treated with CAPZ+CAP.
Figure 7
Figure 7
A, Immunoactive CGRP concentrations in DRG incubated with vehicle or CAP (0.08 μM; 0.3 μM). B, Effects of pretreatment with CAPZ (10 μM), dantrolene (50 μM), TG (2 μM), or 2-APB (100 μM) on CAP (0.3 μM)-induced CGRP release in DRG. n = 6. *P<0.05 compared to corresponding vehicles. †P<0.05 compared to DRG treated with CAP (0.08 μM) in panel A or CAP (0.3 μM) in panel B. # P<0.05 compared to DRG treated with CAPZ+CAP or dantrolene+CAP.
Figure 8
Figure 8
A. Effects of extracellular calcium (Ca2+) on CAP (0.3 μM)-induced CGRP release in DRG. B. Effects of caffeine (20 mM) on CGRP release in DRG. n = 6. *P<0.01 compared to corresponding vehicles. †P<0.01 compared to that in normal Kreb’s solution.
Figure 9
Figure 9
Effects of pretreatment with CAPZ (10 μM), dantrlene (50 uM), thapsigargin (20 uM), or 2-APB (100 uM) on CAP (0.3 uM)-induced intracellular calcium (Ca2+) response. n = 15 to 32. *P<0.05 compared to neurons treated with CAP alone. †P<0.05 compared to neutrons treated with CAPZ+CAP.
Figure 10
Figure 10
Confocal microscopic images of double-immunofluorescence staining of DRG (A—C). A, Cy3-labeled TRPV1 channels stained red. B, FITC-labeled RyR stained green. C, Colocalization of TRPV1 and RyR (yellow). A—C represent the same section of a DRG neuron.
Figure 11
Figure 11
Schematic representation of the potential molecular mechanisms involved in TRPV1-induced CGRP release in sensory neurons. CAP, a selective TRPV1 agonist, binds to TRPV1 on plasma membrane that leads to an increase in Ca2+ influx and activates RyR but not IP3R expressed in ER, resulting in Ca2+ release from ER and consequent CGRP release that in turn activates CGRP receptors (CGRP R) expressed in vascular endothelial cells (EC) or smooth muscle cells (SMC) to cause vasodilation. NO, nitric oxide; BP, blood pressure.
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