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Human Trabecular Meshwork Cells Express Functional Serotonin-2A (5HT_2A) Receptors: Role in IOP Reduction

From Ophthalmology Discovery Research, Alcon Research, Ltd., Fort Worth, Texas.

PURPOSE. To apply a multidisciplinary approach to the identification and pharmacological characterization of the serotonin (5HT) receptors that mediate functional responses in human trabecular meshwork (h-TM) cells. To correlate in vitro findings with intraocular pressure (IOP) changes in conscious ocular hypertensive cynomolgus monkeys.

METHODS. Documented methods were used, including reverse transcription–polymerase chain reaction (RT-PCR), phosphoinositide (PI) turnover, and intracellular Ca²⁺ ([Ca²⁺]_i) mobilization. IOP was measured using standard applanation pneumatonometry.

RESULTS. h-TM cells expressed robust mRNA signals for 5HT_2A and 5HT_2B receptors. 5HT and its analogues stimulated PI turnover and [Ca²⁺]_i mobilization in h-TM cells from multiple donors (20/24 donors’ TM cells responded). The agonist potencies (EC₅₀) of compounds in mobilizing [Ca²⁺]_i were (nM): 5-methoxy tryptamine, 8 ± 4; (R)-DOI, 18 ± 6; -methyl-5HT, 22 ± 3; 5HT, 40 ± 7; 5-methoxy-dimethyl tryptamine, 64 ± 27; and BW-723C86, 1213 ± 210. These effects were potently blocked by the 5HT_2A-receptor-selective antagonist, M-100907 (K_i = 1 ± 0.3 nM), but weakly by antagonists of 5HT_2B and 5HT_2C receptors. Only 5HT₂ receptor agonists such as (R)-DOI (300 µg lowered IOP 34.4% from baseline of 38.2 mm Hg; P < 0.001) and -methyl-5HT (250 µg lowered IOP 30.8% from baseline of 41.8 mm Hg; P < 0.001) lowered IOP in ocular hypertensive cynomolgus monkeys.

CONCLUSIONS. Strong signals for 5HT_2A and 5HT_2B receptor mRNAs were detected in h-TM cells. The receptors that coupled to PI hydrolysis and [Ca²⁺]_i mobilization in h-TM cells were the 5HT_2A receptor subtype, which also significantly lowered IOP in a primate model. These receptors may mediate the ocular hypotensive actions of 5HT_2A agonists.