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a The Molecular Reproduction Research Laboratory and
b the Experimental Hypertension Group, Clinical Research Institute of Montreal, Montreal, Quebec, Canada H2W 1R7
Ovarian granulosa cell and testicular Sertoli cell functions are regulated by the tropic action of the pituitary follicle-stimulating hormone (FSH), which may exert pleiotropic effects using a variety of signaling pathways. The effects of FSH on the mobilization of Ca2+ into granulosa and Sertoli cells have been widely studied, but whether all the effects of the hormone are mediated by the single G-protein-coupled (Gs) receptor with the seven-transmembrane structure (R1) has remained an enigma. With the object of resolving this mystery, we have compared the hormonal responses of HEK 293 cells transfected with three different cloned FSH receptor cDNAs of testis/ovary, designated R1 (Gs), R2 (similar to R1 but having a shorter carboxyl terminus), and R3, a novel FSH receptor exhibiting a growth factor type I receptor motif. The latter two that use the same DNA segment for alternative splicing of the single large 80- to 100-kilobase gene create different structural motifs and carboxyl termini. Of the three receptors, only the FSH-R3 type induced a significant rise in intracellular free calcium concentration ([Ca2+]i), as measured by single cell fluorescence digital imaging with the Ca2+ sensitive dye fura-2AM. FSH induced a rapid [Ca2+]i response that was concentration dependent. The response was hormone-specific, as neither its individual 
/ß subunits nor the related glycoprotein hormone LH were effective. To determine whether the [Ca2+]i response was due to Ca2+ influx or to intracellular Ca2+ mobilization, cells were exposed to Ca2+-free buffer and to the Ca2+-channel blocker diltiazem (10-5 M). FSH-Induced [Ca2+]i responses were inhibited in Ca2+-free buffer and abrogated in the presence of diltiazem. These novel data demonstrate that FSH can increase [Ca2+]i through L-type voltage-dependent Ca2+ channels via the growth factor type 1 receptor. Our findings support the concept that different receptor motifs act to integrate intracellular signaling events.
1 This investigation was supported by grants from the Medical Research Council of Canada. R.M.T. is a scholar of the Fonds de la Recherche en Santé du Québec.
2 Correspondence: M. Ram Sairam, Molecular Reproduction Research Laboratory, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, PQ, Canada H2W 1R7. FAX: 514 987 5585; sairamm{at}ircm.qc.ca
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