Abstract
The L-α-lysophosphatidylinositol (LPI)-sensitive receptor GPR55 is coupled to Ca(2+) signaling. Low levels of GPR55 expression in the heart have been reported. Similar to other G protein-coupled receptors involved in cardiac function, GPR55 may be expressed both at the sarcolemma and intracellularly. Thus, to explore the role of GPR55 in cardiomyocytes, we used calcium and voltage imaging and extracellular administration or intracellular microinjection of GPR55 ligands. We provide the first evidence that, in cultured neonatal ventricular myocytes, LPI triggers distinct signaling pathways via GPR55, depending on receptor localization. GPR55 activation at the sarcolemma elicits, on one hand, Ca(2+) entry via L-type Ca(2+) channels and, on the other, inositol 1,4,5-trisphosphate-dependent Ca(2+) release. The latter signal is further amplified by Ca(2+)-induced Ca(2+) release via ryanodine receptors. Conversely, activation of GPR55 at the membrane of intracellular organelles promotes Ca(2+) release from acidic-like Ca(2+) stores via the endolysosomal NAADP-sensitive two-pore channels. This response is similarly enhanced by Ca(2+)-induced Ca(2+) release via ryanodine receptors. Extracellularly applied LPI produces Ca(2+)-independent membrane depolarization, whereas the Ca(2+) signal induced by intracellular microinjection of LPI converges to hyperpolarization of the sarcolemma. Collectively, our findings point to GPR55 as a novel G protein-coupled receptor regulating cardiac function at two cellular sites. This work may serve as a platform for future studies exploring the potential of GPR55 as a therapeutic target in cardiac disorders.
Highlights
The LPI-sensitive receptor GPR55 signals through Ca2ϩ
Extracellular Administration of LPI Elicits GPR55-dependent Cytosolic Ca2ϩ Elevation in Ventricular Cardiomyocytes, Which Is Partially Contingent on Ca2ϩ Entry—To initially determine whether GPR55 activation can elevate cytosolic Ca2ϩ in cultured neonatal ventricular myocytes, the cells were stimulated with increasing concentrations of LPI in the absence and presence of a GPR55 antagonist
In addition to the “classical” G protein-coupled receptors (GPCRs) involved in heart function, such as those for angiotensin II, endothelin 1, or catecholamines [48, 49], a wide variety of recently deorphanized GPCRs are expressed in cardiac cells [50]
Summary
The LPI-sensitive receptor GPR55 signals through Ca2ϩ. Results: Activation of sarcolemmal versus intracellular GPR55 mobilizes Ca2ϩ from distinct pools and associates with cardiomyocyte depolarization and hyperpolarization, respectively. Activation of GPR55 at the membrane of intracellular organelles promotes Ca2؉ release from acidic-like Ca2؉ stores via the endolysosomal NAADP-sensitive two-pore channels This response is enhanced by Ca2؉-induced Ca2؉ release via ryanodine receptors. Additional functional implications of GPR55 may be inferred from its widespread distribution throughout the body [8, 9], including the heart [8] It serves as target for several cannabinoid ligands, GPR55 appears to be endogenously activated by L-␣-lysophosphatidylinositol (LPI)4 [10, 11]. We used Ca2ϩ and voltage imaging and both extracellular and intracellular administration (microinjection) of GPR55 ligands to test the involvement of this receptor in the regulation of cardiomyocyte signaling
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