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From the Reproductive Immunology and Molecular Biology Laboratories, Department of Obstetrics and Gynecology, West Virginia University, School of Medicine, Morgantown, West Virginia.
| Correspondence to: Dr Rajesh Naz, Robert C. Byrd Health Sciences Center North, Room 2084, West Virginia University, School of Medicine, Morgantown, WV 26505-9186 (e-mail: rnaz{at}hsc.wvu.edu). |
| Received for publication June 1, 2006; accepted for publication June 1, 2006. |
Results and Discussion
Hormone Receptors—
Various hormone receptors which have been delineated in sperm are
summarized in Table 1.
|
Gonadotropin-Releasing Hormone Receptor. Gonadotropin-releasing hormone (GnRH) is a decapeptide released from the hypothalamus which binds to membrane-bound receptors in the anterior pituitary for secretion of gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) (Clayton, 1989). GnRH-R cDNA has been cloned from mouse, rat, and human tissues (Tsutsumi et al, 1992; Chi et al, 1993; Perrin et al, 1993). The cognate GnRH-R has a molecular mass of approximately 50 to 60 kd. Besides anterior pituitary, GnRH-R is present in other tissues. GnRH-R of 45 kd has also been reported in ejaculated human sperm (Lee et al, 2000). Incubation of human sperm with GnRH increases sperm binding with human oocyte zona pellucida in the hemizona assay (Morales, 1998). GnRH antagonist completely inhibits the enhancing effect. There is no effect of GnRH on sperm capacitation and/or acrosomal exocytosis. It is hypothesized that increased sperm binding to oocytes is due to exposure and/or change in affinity of zona receptors on sperm membranes.
Luteinizing hormone/human chorionic gonadotropin receptor. LH is a
glycoprotein secreted by the anterior pituitary. It has 2 polypeptides,
and ß chains. The chain is common among
thyroid-stimulating hormone, FSH, LH, and human chorionic gonadotropin (hCG),
and the ß chain is specific to each hormone. The ß chain of LH has
more than 80% sequence homology with the ß chain of hCG. hCG is primarily
produced by the placenta. Apart from the anterior pituitary and placenta,
small amounts of LH/hCG are also produced by other tissues, including the
testis and fallopian tube (Chowdhury and
Steinberger, 1979; Lei et al,
1993; Berger et al,
1994). Both LH and hCG interact with the same membrane receptors
that are present in Leydig cells and other tissues. The functional LH/hCG
hormone receptors (both mRNA and protein) are also present in head, midpiece,
and tail regions of human ejaculated sperm
(Eblen et al, 2001). The mRNA
transcript was detected by reverse transcriptase-polymerase chain reaction
(RT-PCR), and Western blot and radiolabeled 125I-hCG binding
delineated an 80-kd receptor protein. Addition of 100 ng/mL hCG or LH to human
sperm activates protein kinase A (not protein kinase C) and increases
intracellular cyclic adenosine monophosphate (cAMP) levels
(Eblen et al, 2001).
Interestingly, both males and females of the gene knockout mice of the LH/hCG
receptor are infertile (Lei et al,
2001).
Estrogen Receptor. Estrogen is also produced in males and affects
reproduction (Hess et al,
1997). In males, it is present in low concentrations in blood but
is present at extraordinarily high levels in semen. Estrogen effects are
mediated by 2 distinct nuclear receptors, estrogen receptor
(ER) and ERß. The receptors are encoded by 2 different genes and
are expressed in germ cells (O'Donnell et
al, 2001). Besides the genomic effect mediated by the 2 nuclear
receptors, estrogen also causes nongenomic effects mediated through membrane
receptors. Rapid nongenomic effects of estrogen have been demonstrated in
several cells (Ho and Liao,
2002) and are mediated by specific membrane receptors.
Transfection studies of ER cDNA indicate that both membrane and nuclear
receptors originate from a single transcript
(Razandi et al, 1999).
An earlier study demonstrated the presence of estrogen binding sites on
human spermatozoa (Cheng et al,
1981). Immunofluorescence labeling, confocal laser scanning
microscopy, and Western blot analysis verified that ER (45, 66 kd) is
present in postacrosomal, midpiece and tail regions, and ERß (64 kd) in
midpiece and tail regions and mitochondria of ejaculated human sperm
(Durke et al, 1998;
Aquila et al, 2004;
Solakidi et al, 2005).
Transcripts of both receptors are also present in ejaculated human sperm.
Incubation of sperm with 17-ß-estradiol affects capacitation, acrosomal
exocytosis, and fertilizing ability (Adeoya-Osigawa et al, 2003). Estrogen
stimulates phosphorylation of proteins involved in the
phosphatidylinositol-3-OH kinase/Akt pathway and stimulates ERK1/2, which is
involved in sperm function (Luconi et al,
1999; Aquila et al,
2004; Luconi et al,
2004). ER gene knockout male mice are infertile, have
reduced mating behavior, and produce poor-quality sperm
(Eddy et al, 1996). However,
ERß knockout male mice are fertile and exhibit normal sexual behavior but
have fewer and smaller litters (Krege et
al, 1998).
Androgen Receptor. Androgens are steroid hormones that are important for development of secondary sex characteristics and initiation and maintenance of spermatogenesis. These are genomic effects, mediated through nuclear receptors (Lindzey et al, 1994). However, nongenomic effects of androgen have been described which are nontranscriptional and mediated through membrane receptors (Walker, 2003).
The presence of testosterone binding sites have been demonstrated on sperm and correlated with motility (Warikoo et al, 1986). Recently immunofluorescence labeling and confocal microscopy localized androgen receptors (ARs) in midpiece and mitochondria of ejaculated human sperm. Western blot analysis using AR antibodies specifically detected 110- and 90-kd protein bands, corresponding to AR (Solakidi et al, 2005). Tissue-specific AR gene knockout in Sertoli cells affects androgen function and causes infertility due to an arrest in spermatogenesis (Chang et al, 2004).
Progesterone Receptor. Progesterone, a female hormone, is also involved in male reproduction. The physiologic responses to progesterone are mediated through 2 types of nuclear receptors, progesterone receptor A (PR-A) and PR-B. These 2 classic nuclear receptors are encoded by a single gene (Gadkar-Sable et al, 2005). Besides nuclear receptor binding, progesterone also binds on sperm surfaces through specific receptors (Ambhaikar and Puri, 1998). These receptors are localized on the membrane and are unrelated to the classic receptors.
Western blot analysis with peroxidase-conjugated progesterone detected 2 progesterone-binding proteins of 54 and 57 kd in lysate of human sperm. These 2 receptors are present on membranes but not in the cytoplasm (Luconi et al, 1998). In boar sperm, a 71-ka PR protein has been delineated (Jang and Yi, 2005); in canine sperm, 2 proteins of 54 and 65 kd have been found that bind to progesterone (Wu et al, 2005). These differences in molecular mass of progesterone-binding proteins among various species may be due to species differences and/or methods of sperm lysate preparation. Progesterone mRNA transcripts have also been detected in sperm (Sachdeva et al, 2000). Progesterone-bovine serum albumin-fluorescein isothiocyanate conjugate identified PRs in the acrosome (Ambhaikar and Puri, 1998; Sachdeva et al, 2005; Wu et al, 2005), equatorial, and postacrosomal regions of sperm (Jacob et al, 1998; Contreras and Llanos, 2001). Incubation of sperm with progesterone affects sperm motility, capacitation, and acrosomal exocytosis (Baldi et al, 1998, 1999; Contreras and Llanos, 2001; Wu et al, 2005). Experiments have demonstrated that progesterone stimulates sperm motility and acrosome reaction in a dose-dependant manner.
Leptin Receptor. Leptin is a 16-kd protein secreted by adipose tissue (Zhang et al, 1994). Its role has been implicated in reproduction (Ahima and Flier, 2000). Leptin acts on target tissues via membrane-bound receptors (Tartaglia et al, 1995). These receptors are classified into long form and short form (Tartaglia, 1997). Leptin and its receptors are present in testes (Tena-Sempere et al, 2001), and leptin has been detected in seminal plasma (Glander et al, 2002). Leptin levels in seminal plasma are negatively correlated with sperm progressive motility. Leptin receptor (145-kd protein) is present in the tail region of ejaculated spermatozoa (Jope, 2003). The exact isoform has not been delineated.
Calcitonin Receptor. Calcitonin is a 32-amino acid peptide hormone that regulates calcium homeostasis. Calcitonin is present in seminal plasma, and its receptors exist in spermatozoa (Sjoberg et al, 1980; Silvestroni et al, 1987). Calcitonin receptors are present in acrosomal, midpiece, and tail regions of spermatozoa (Adeoya-Osiguwa and Fraser, 2003). Calcitonin stimulates cAMP production in noncapacitated sperm (Adeoya-Osiguwa and Fraser, 2003).
Cytokine Receptors— Various cytokine and growth factor receptors that have been delineated in sperm are summarized in Table 2.
|
Interferon and 
Receptors. Interferons (IFNs) are a
heterogenous family of proteins that have the ability to protect body cells
from viral infection (Friedmann,
1990). IFN is produced by peripheral blood mononuclear
cells in response to viral infection, and IFN is produced by T
lymphocytes and natural killer cells
(Biron et al, 1999). IFN
receptors have been cloned and characterized: IFN receptor is
68.5/95–100 kd and IFN receptor is 48.8–52.5/90 kd (Farrar
and Shreiber, 1993; Constantinescu et al,
1994). Indirect immunofluorescence, immunoscanning electron
microscopic, immunoprecipitation, and Western blot procedures localized IFN
and receptors of similar molecular masses in acrosomal,
midpiece, and tail regions of spermatozoa of several mammalian species,
including humans (Naz et al,
2000). Incubation of spermatozoa with IFNs decreases sperm
motility (Naz and Kumar,
1991).
Interleukin 2 and ß Receptors. Flow cytometry and
transmission electron microscopy detected interleukin 2 (IL2) and
ß receptors in head and midpiece regions of human spermatozoa; these
receptors have shown some correlation with sperm concentration in semen
(Fierro et al, 2002).
Interleukin 3 and 5 Receptors. IL3 and IL5 belong to the cytokine family that regulates proliferation and differentiation of hematopoietic cells. There are 2 types of receptors for each cytokine that show high or low affinity for the ligand depending on their subunit composition. Immunolocalization study demonstrated the presence of these receptors in ejaculated bovine spermatozoa (Rauch et al, 2004). Functional studies indicate that IL3 but not IL5 signals an increased uptake of hexose in sperm cells at picomolar concentrations compatible with expression of IL3 receptors (Rauch et al, 2004).
Interleukin 6 Receptors. IL6, belonging to the hematopoietic
cytokine family, is a mediator of inflammatory response and is present in
female and male reproductive tract secretions
(Kishimoto, 1989; Naz and
Kaplan, 1994a,
b). Its biologic effects are
mediated by binding to specific receptors IL6 R and ß
(Kishimoto, 1989). IL6 R
of 80 kD has been localized in tail region of human sperm
(Laflamme et al, 2005). IL6 is
present in human semen and incubation of sperm with IL6 enhances their
fertilizing capacity by increasing capacitation and/or acrosomal exocytosis
(Naz and Kaplan 1994a,
b). IL6 stimulates
capacitation by increasing phosphorylation of tyrosine kinase JAK1
(Laflamme et al, 2005).
Granulocyte Macrophage Colony-Stimulating Factor Receptor.
Immunocytochemical studies localized granulocyte macrophage colony-stimulating
factor (GM-CSF) (45 and 82 kd) and ß (105–110 kd) receptors
to the tail regions of ejaculated human spermatozoa
(Zambrano et al, 2001).
Incubation with GM-CSF increases uptake of deoxy glucose and deoxy ascorbic
acid (Zambrano et al,
2001).
ß Chemokine Receptors. ß Chemokine RANTES (regulated on activation, normal T expressed and secreted) is a 68-amino acid polypeptide belonging to the chemokine subgroup. It has chemotactic effect (He et al, 1997) and is present in male and female reproductive tract secretions (Hornung et al, 2001; Naz and Leslie, 2000). It binds to receptors, CCR1, CCR3, CCR4, and CCR5 (Rollins, 1997). CCR5 is localized in the periacrosomal regions, and CCR3 is present in the postacrosomal regions of ejaculated human sperm (Muciaccia et al, 2005). mRNA transcripts for CCR1 and CCR5 have also been detected in human sperm (Isobe et al, 2002).
Epidermal Growth Factor Receptor. Epidermal growth factor (EGF) is a 53-amino acid polypeptide present in many tissues and body fluids (Savage et al, 1972; Hirata and Orth, 1979). Mitogenic activity of EGF is mediated through a membrane-bound glycoprotein receptor of 170 kd. EGF receptor has been localized in acrosomal, postacrosomal, and tail regions of human and bull sperm (Naz and Ahmad, 1992; Damjanov et al, 1993; Lax et al, 1994). EGF affects sperm capacitation and acrosomal exocytosis through activation of tyrosine kinase (Furuya et al, 1993; Naz and Kaplan, 1993; Lax et al, 1994).
Insulin-Like Growth Factor I Receptor. Insulin-like growth factor I (IGFI) is present in seminal plasma of humans and bulls and oviductal fluids of pigs (Glander et al, 1996). The source of IGFI in seminal plasma is not known, but oviductal epithelial cells secret IGFI. IGFI receptor has been characterized using a radio-receptor assay and localized to the acrosomal region of sperm head by immunohistochemistry (Henricks et al, 1998). The same study demonstrated the interaction of IGFI ligand with its receptor in sperm. Sperm treated with IGFI (100 ng/mL) and IGFII (250 ng/mL) increased motility and straight-line velocity (Henricks et al, 1998). Mice homozygous for a targeted mutation of the IgfI gene are infertile dwarfs with smaller testes (Baker et al, 1996).
Neurotransmitter Receptors— Various neurotransmitter receptors which have been delineated in sperm are summarized in Table 3.
|
Aminobutyric Acid Receptors. Aminobutyric acid
(GABA) is an inhibitory neurotransmitter present in the central nervous system
(Krnjevic et al, 1974). It has
also been shown to be present in rat oviduct and human seminal plasma
(Martin del Rio, 1981;
Ritta et al, 1998). GABA A
receptor is present in the equatorial segment of human spermatozoa
(Wistrom and Meizel, 1993;
Ritta et al, 1998). Incubation
of human sperm with GABA at high concentration causes hyperactivated
motility.
Glycine Receptor. Glycine is an inhibitory neurotransmitter that
acts through membrane-bound glycine receptors. Glycine receptor is comprised
of and ß subunits and forms pentameric Cl-channels
(Rajendra et al, 1997).
Glycine receptors of 49 and 50 kd are present in the periacrosomal region of
sperm plasma membrane (Melendrez and
Meizel, 1996). Incubation with glycine induces acrosomal
exocytosis, which is inhibited by strychnine, a glycine receptor antagonist
(Melendrez and Meizel,
1995).
Nicotinic Acetylcholine Receptor. Nicotinic acetylcholine receptor
(nAch R) is present in the head and tail regions of spermatozoa (Young and
Liang, 1991). Western blot and immunofluorescence studies detected the nACh R
subunits 3, 5, 7, 9, and ß4 in sperm
(Kumar and Meizel, 2005).
Acetylcholine induces acrosomal exocytosis in capacitated sperm. Acrosomal
exocytosis of human sperm induced by human recombinant ZP3 is blocked by
nicotinic antagonist (Bray et al,
2002).
Miscellaneous Receptors— Various miscellaneous receptors which have been delineated in sperm are summarized in Table 4.
|
Platelet-Activating Factor Receptor. Platelet-activating factor (PAF) (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is involved in diverse functions of various tissues (Snyder, 1990). PAF is found in spermatozoa (Minhas et al, 1991). Immunofluorescence demonstrated the presence of PAF receptors, mostly in the midpiece and proximal head regions of ejaculated spermatozoa. (Reinhardt et al 1999; Roudesbush et al 2000). Immunofluorescence microscopy and quantitative RT-PCR detected an altered pattern of PAF receptor distribution and its mRNA in abnormal spermatozoa, compared with normal sperm. PAF stimulates human sperm motility, stimulates sperm penetration of cervical mucus, and increases human sperm penetration rates in zona-free hamster oocytes (Minhas, 1993).
Angiotensin II Receptors. The peptide hormone, angiotensin II, acts as a modulator of many cell physiologic functions, which are mediated through binding to 2 distinct receptors: angiotensin II type 1 (AT1) and type 2 (AT2) receptors (Griendling et al, 1996). Follicular fluid is one of the endogenous sources of angiotensin II (Heimler et al, 1995). Immunocytochemical and immunoblotting techniques identified the AT1 receptor protein of 60 kd in tail regions of ejaculated human sperm (Vinson et al, 1995), and a 41-kd protein in head and tail regions of bovine spermatozoa (Gur et al, 1998). Incubation of sperm with angiotensin II increases sperm motility (Vinson et al, 1995) and induces acrosomal exocytosis (Gur et al, 1998).
Odorant Receptor. Discovery of the odorant receptor (OR) gene family has revolutionized the field of chemosensation (Buck and Axel, 1991) and led to understanding of the olfactory system. Sensory system olfactory receptors have been cloned, and their mRNA transcripts have been detected in several tissues (Spehr et al, 2006). OR of 40 kd is present in tail and midpiece regions of ejaculated dog sperm (Vanderhaeghen et al, 1993). Recently human testicular OR, hOR17-4, was cloned and characterized (Spehr et al, 2003). When it was expressed in human embryonic kidney cells and tested with an odorant, bourgeonal, there was an increase in intracellular calcium level. It has been suggested that ORs play an important chemotactic role in bringing sperm to oocyte.
Atrial Natriuretic Factor Receptor. Atrial natriuretic factor (ANF), a 28-amino acid peptide, is secreted by the cardiac atrium and regulates body fluid homeostasis (Brenner et al, 1990). ANF is present in follicular fluid (Steegers et al, 1990). ANF receptor of 135–140 kd has been detected in the midpiece region of spermatozoa (Silvestroni et al, 1992). ANF stimulates acrosomal exocytosis that is inhibited by its antagonist, anantin (Rotem et al, 1998).
Decapacitation Factor Receptor. Decapacitation factor (DF) is a 40-kd protein that prevents capacitation when it binds to sperm (Fraser et al, 1990). DF binds with a specific decapacitation factor receptor (DFR) present on sperm surfaces. Recently it was found that DFR, a 23-kd protein, is a phosphatidylethanolamine-binding protein 1 (PEBP1), localized in acrosomal, postacrosomal, and tail regions of sperm (Gibbons et al, 2005). Incubation of sperm with DF and PEBP1 causes a loss of decapacitating activity.
Conclusions
There are numerous receptors, including 8 hormone receptors, 16
cytokine/growth factor receptors, 3 neurotransmitter receptors, and 5
miscellaneous receptors, that have been reported to be present in mature
ejaculated sperm. The list is ever growing. Almost all of these receptors have
been shown to be involved, directly or indirectly, in sperm capacitation
and/or acrosomal exocytosis in in vitro studies. Do these receptors have a
physiologic significance in vivo? It seems doubtful that all of these
receptors are really involved in affecting sperm capacitation/acrosomal
exocytosis in vivo due to the following facts:
In conclusion, receptors for several hormones, cytokines, growth factors, and neurotransmitters have been reported and/or are being reported in mature ejaculated sperm cells. Their authenticity and in vivo physiologic relevance need to be carefully examined before making conclusions that they are real and functionally important.
Acknowledgments
We thank Maegan Cook and Ashleigh Pegg for providing excellent typing assistance.
Footnotes
Supported in part by a grant (HD24425) from the National Institutes of Health.
DOI: 10.2164/jandrol.106.000620
* Andrology Lab Corner welcomes the submission of unsolicited
manuscripts, requested reviews, and articles in a debate format. Manuscripts
will be reviewed and edited by the Section Editor. All submissions should be
sent to the Journal of Andrology Editorial Office. Letters to
the editor in response to articles as well as suggested topics for future
issues are encouraged. 
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