IP3R Channels in Male Reproduction

Abstract

As a second messenger in cellular signal transduction, calcium signaling extensively participates in various physiological activities, including spermatogenesis and the regulation of sperm function. Abnormal calcium signaling is highly correlated with male infertility. Calcium signaling is mainly regulated by both extracellular calcium influx and the release of calcium stores. Inositol 1,4,5-trisphosphate receptor (IP3R) is a widely expressed channel for calcium stores. After being activated by inositol 1,4,5-trisphosphate (IP3) and calcium signaling at a lower concentration, IP3R can regulate the release of Ca²⁺ from stores into cytoplasm, and eventually trigger downstream events. The closure of the IP3R channel caused by a rise in intracellular calcium signals and the activation of the calcium pump jointly restores the calcium store to a normal level. In this review, we aim to discuss structural features of IP3R channels and the underlying mechanism of IP3R channel-mediated calcium signaling and further focus on the research progress of IP3R expression and function in the male reproductive system. Finally, we propose key directions and strategies for research of IP3R in spermatogenesis and the regulation of sperm function to provide more understanding of the function and mechanism of IP3R channel actions in male reproduction.

Keywords: IP3R; calcium signaling; infertility; male reproduction; sperm function; spermatogenesis.

Figure 1

Diagram of the structure and regulation of the inositol 1,4,5-trisphosphate receptor (IP3R) channel. (A) Five domains of IP3R. (B) Regulation of IP3R by IP3, Ca²⁺ and interaction proteins.

Figure 2

mRNA expression levels of inositol 1,4,5-trisphosphate receptors (IP3Rs) in human (A) and mouse (B) testes at different stages of development. The data were obtained from the ArrayExpress database (E-MTAB-6814 and E-MTAB-6798). Fragments Per Kilobase Million (FPKM) values from RNA-seq experiments were used to indicate the mRNA expression levels of IP3Rs.

Figure 3

mRNA expression levels of inositol 1,4,5-trisphosphate receptors (IP3Rs) in mouse spermatogenic cells. Spermatogonia (Spg), preleptotene (PL), leptotene (L), zygotene (Z), pachytene (P), diplotene (D), secondary spermatocytes (MII), round spermatids (RSs), and elongated spermatids (ES) were sorted by flow cytometry with Hochest33342/propidium staining. Total RNA was used to analyze mRNA expression levels of IP3R1, IP3R2 and IP3R3 by qPCR. β-actin served as an internal control to normalize the gene expression levels.