Calcium-Sensing Receptor Regulates Cytosolic [Ca 2+ ] and Plays a Major Role in the Development of Pulmonary Hypertension

• Published in: Frontiers in physiology Vol. 7; p. 517
• Main Authors: Smith, Kimberly A, Ayon, Ramon J, Tang, Haiyang, Makino, Ayako, Yuan, Jason X-J
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 04-11-2016
• Subjects: Ca2+-sensing receptor; G-protein-coupled receptor; Physiology; pulmonary arterial hypertension; Pulmonary Artery; smooth muscle cells; Store-operated channels; smooth muscle cells; pulmonary artery; G-protein coupled receptor; pulmonary arterial hypertension; store-operated calcium channel; Ca2+-sensing receptor
• ISSN: 1664-042X; 1664-042X
• DOI: 10.3389/fphys.2016.00517

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary vascular resistance (PVR) leading to right heart failure and premature death. The increased PVR results in part from pulmonary vascular remodeling and sustained pulmonary vasoconstriction. Excessive pulmonary vascular remodeling stems from increased pulmonary arterial smooth muscle cell (PASMC) proliferation and decreased PASMC apoptosis. A rise in cytosolic free Ca
concentration ([Ca
]
) in PASMC is a major trigger for pulmonary vasoconstriction and a key stimulus for PASMC proliferation and migration, both contributing to the development of pulmonary vascular remodeling. PASMC from patients with idiopathic PAH (IPAH) have increased resting [Ca
]
and enhanced Ca
influx. Enhanced Ca
entry into PASMC due to upregulation of membrane receptors and/or Ca
channels may contribute to PASMC contraction and proliferation and to pulmonary vasoconstriction and pulmonary vascular remodeling. We have shown that the extracellular Ca
-sensing receptor (CaSR), which is a member of G protein-coupled receptor (GPCR) subfamily C, is upregulated, and the extracellular Ca
-induced increase in [Ca
]
is enhanced in PASMC from patients with IPAH in comparison to PASMC from normal subjects. Pharmacologically blockade of CaSR significantly attenuate the development and progression of experimental pulmonary hypertension in animals. Additionally, we have demonstrated that dihydropyridine Ca
channel blockers (e.g., nifedipine), which are used to treat PAH patients but are only effective in 15-20% of patients, activate CaSR resulting in an increase in [Ca
]
in IPAH-PASMC, but not normal PASMC. Our data indicate that CaSR functionally couples with transient receptor potential canonical (TRPC) channels to mediate extracellular Ca
-induced Ca
influx and increase in [Ca
]
in IPAH-PASMC. Upregulated CaSR is necessary for the enhanced extracellular Ca
-induced increase in [Ca
]
and the augmented proliferation of PASMC in patients with IPAH. This review will highlight the pathogenic role of CaSR in the development and progression of PAH.