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OR1D2 Receptor Mediates Bourgeonal-Induced Human Catsper Activation in a G-Protein Dependent Manner

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OR1D2 Receptor Mediates Bourgeonal-Induced Human Catsper Activation in a G-Protein Dependent Manner bioRxiv preprint doi: https://doi.org/10.1101/757880; this version posted September 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 2 3 4 OR1D2 receptor mediates bourgeonal-induced human 5 CatSper activation in a G-protein dependent manner 6 7 a a c 8 Yi-min Cheng , Tao Luo , Zhen Peng , d e a,b,1 9 Hou-yang Chen , Jin Zhang , Xu-Hui Zeng 10 11 12 a Institute of Life Science and School of Life Science, Nanchang University, 13 Nanchang, Jiangxi, 330031, PR China 14 b Institute of Reproductive Medicine, School of Medicine, Nantong University, 15 Nantong, Jiangsu, 226000, PR China 16 c Department of Pharmacy, the First People’s Hospital of Yichun City, Yichun, 17 Jiangxi, 336000, PR China 18 d Reproductive Medical Center, Jiangxi Provincial Maternal and Child Health 19 Hospital, Nanchang, Jiangxi, 330006, PR China 20 e School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi, 21 330031, PR China 22 1 To whom correspondence should be addressed. E-mail: [email protected] 23 24 25 Running title: OR1D2 is involved in CatSper activation 26 27 28 Key words: human CatSper / OR1D2 receptor / G protein / cAMP / Sperm chemotaxis 29 30 31 The character count：46171 32 1 bioRxiv preprint doi: https://doi.org/10.1101/757880; this version posted September 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 33 Abstract 34 During fertilization, sperm are guided towards eggs by physiological chemokines, a 35 process named sperm chemotaxis. Human sperm chemotaxis is speculated to be 36 mediated by olfactory receptor OR1D2 in a pathway requiring calcium influx. 37 Bourgeonal, an artificial ligand of OR1D2, can activate CatSper, the primary calcium 38 channel in human sperm. However, whether bourgeonal-induced CatSper activation 39 requires OR1D2 and how CatSper is activated remain unclear. Herein, we show that 40 OR1D2 antibody can inhibit bourgeonal-induced CatSper activation and sperm 41 chemotaxis, proving that OR1D2 mediates bourgeonal-induced CatSper activation. 42 Furthermore, bourgeonal-evoked CatSper currents can be greatly suppressed by either 43 GDP-β-S or antibody of Gαs. Interestingly, bourgeonal can transiently increase sperm 44 cAMP level, and this effect can be abolished by OR1D2 antibody. Consistently, 45 bourgeonal-induced CatSper activation can be inhibited by membrane adenylate 46 cyclases inhibitor. Overall, our results indicate that bourgeonal activates CatSper via 47 OR1D2-G protein-cAMP pathway. Although CatSper can be activated by various 48 physiological and environmental factors, this study represents the most recent 49 progress proving that CatSper can be indirectly activated by extracellular regulators 50 through a G-protein-dependent intracellular signaling pathway. 51 52 Introduction 53 Mammalian sperm need to be guided towards eggs by various mechanisms, 54 including thermotaxis (1), rheotaxis (2) and chemotaxis (3), which is defined by 55 moving up a concentration gradient of chemokines. Mammalian sperm chemotaxis 56 was initially described 68 years ago (4). To date, some physiological chemokines, 57 such as progesterone (5) and atrial natriuretic peptide (6), have been identified in 58 mammalian follicular fluid and cumulus cell secretions, suggesting that chemotaxis is 59 a short-range mechanism acting near the fertilization site to guide sperm to the egg (7). 60 Although the signaling pathways of mammalian sperm chemotaxis are far from being 61 defined, one candidate, the olfactory receptor OR1D2 (olfactory receptor family 1 62 subfamily D member 2, aliases: hOR17-4), has been proposed to play an important 63 role in human sperm chemotaxis (8). 64 Although 1.4%-4% of all human genes encode olfactory receptors (ORs) (9), two 65 thirds of them show sequence disruption, leaving about 350 functional ORs (10, 11). 66 Surprisingly, the expression of functional ORs is not tightly restricted to olfactory 67 sensory neurons. For example, some ORs have been identified in early stage germ 68 cells and mature sperm of rats and dogs (12, 13), suggesting potential roles of ORs in 69 the mammalian reproductive system. In 2003, the mRNA transcript of OR1D2 was 70 identified in human testis. More importantly, bourgeonal, a synthetic ligand of 2+ 71 OR1D2, was shown to increase human sperm [Ca ]i (cytosolic free calcium 72 concentration) and induce sperm chemotatic movement (8). In the follow-up studies, 73 although other OR members (OR7A5/OR4D1) have been identified in human testis, 74 there is no evidence supporting their involvement in the regulation of human sperm 2 bioRxiv preprint doi: https://doi.org/10.1101/757880; this version posted September 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 75 chemotaxis (14). Therefore, OR1D2 receptor remains the only candidate as a mediator 76 of human sperm chemotaxis, although the consequent signaling after OR1D2 77 activation remain unclear. 2+ 78 In sea urchin, regulation of [Ca ]i fluctuations is the key feature of sperm 79 chemotaxis (15, 16). Bourgeonal-induced human sperm chemotaxis also requires 80 calcium influx (8), suggesting that calcium channels play key roles in human sperm 81 chemotaxis. Although various calcium channels have been proposed to be present in 82 human sperm (17), only CatSper, the sperm specific calcium channel, has been 83 confirmed by patch clamping (18-21). Notably, CatSper gene deletion in both mice 84 and humans produces male infertility, indicating the vital role of CatSper (22-26). It 85 has been proposed that bourgeonal activates human sperm CatSper (27), although 86 whether OR1D2 is necessary for bourgeonal to activate CatSper remains unclear. 87 Since ORs usually transfer extracellular signals through G-protein dependent 88 signaling pathways (11, 28), the involvement of molecules in the G-protein pathways 89 should be expected in bourgeonal-mediated effects, if bourgeonal indirectly activates 90 CatSper through binding with OR1D2. However, 250 μM GDP-β-S showed no 91 inhibitory effect on bourgeonal-induced CatSper activation (27). In addition, no 92 significant increase of cAMP concentration in human sperm had been detected after 93 bourgeonal incubation (27). Those results led to the proposal that bourgeonal may 94 activate CatSper directly (27), raising the question whether OR1D2 participates in the 95 bourgeonal-induced human sperm chemotaxis. 96 Because CatSper is present in species ranging from lower invertebrates to higher 97 mammals and plays crucial role in sperm function regulation (19, 29), the activation 98 mechanism of CatSper has drawn intensive attention. Besides intrinsic pH and voltage 99 sensitivities (19, 20, 21, 30, 31), CatSper can be activated by a variety of 100 physiological and environmental factors (27, 32), which had all been proposed to 101 activate CatSper directly, leading to the idea that CatSper is a poly-modal sensor (27). 102 Interestingly, recently progesterone has been shown to increase CatSper current by 103 activating orphan enzyme alpha/beta hydrolase domain containing protein 2 (ABHD2) 104 to remove an endogenous inhibitory effect of endocannabinoid 105 2-arachidonoylglycerol (2-AG) on CatSper (33). Nevertheless, the studies above 106 suggest that intracellular signaling pathways are not involved in the activation of 107 CatSper by extracellular signaling molecules. 108 Apart from OR1D2, some other G-protein coupled receptors (GPCRs) have been 109 reported to exert regulatory effects on human sperm function, for instance, CCR6 (34) 110 and G protein-coupled receptor 18 (GPR18) (35). In addition, the presence of key 111 components in G protein-dependent pathways, such as stimulatory subunits Golf, Gαs 112 and mAC (membrane adenylate cyclase) Ⅰ-Ⅸ, has been confirmed by multiple 113 techniques in human sperm (36, 37), suggesting a potential role of G-protein 114 dependent signaling in regulating human sperm function. Thus, clarification of 115 whether OR1D2 is necessary for bourgeonal to activate CatSper is not only critical for 116 understanding the chemotaxis mechanism in human sperm, but may also offer insight 117 into how CatSper is activated by extracellular stimuli in general. 118 In this study, OR1D2 antibody was applied to investigate whether OR1D2 is 3 bioRxiv preprint doi: https://doi.org/10.1101/757880; this version posted September 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 119 required for bourgeonal to activate CatSper and induce chemotaxis in human sperm. 120 Furthermore, the potential involvement of intracellular signaling pathway in 121 bourgeonal-induced CatSper activation has also been explored. Our results indicate 122 that OR1D2 mediates bourgeonal-induced CatSper activation through a G-protein 123 dependent manner. This study demonstrates that OR1D2-G protein-cAMP pathway is 124 involved in human sperm chemotaxis regulation, and even more importantly, it 125 provides an example that intracellular signaling pathways must be taken into 126 consideration when studying the mechanisms by which CatSper is activated by 127 extracellular stimuli. 128 Results 129 OR1D2 is distributed along the flagellum of human sperm 130 In previous studies, the expression of OR1D2 mRNA transcript in human testis (8) 131 and the location of OR1D2 in mature human sperm (38) had already been identified. 132 In the present study, the presence of OR1D2 in sperm was further examined by 133 immunoblotting.
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