Regulation and roles of Ca2+ stores in human sperm

Abstract

[Ca(2)(+)]i signalling is a key regulatory mechanism in sperm function. In mammalian sperm the Ca(2)(+)-permeable plasma membrane ion channel CatSper is central to [Ca(2)(+)]i signalling, but there is good evidence that Ca(2)(+) stored in intracellular organelles is also functionally important. Here we briefly review the current understanding of the diversity of Ca(2)(+) stores and the mechanisms for the regulation of their activity. We then consider the evidence for the involvement of these stores in [Ca(2)(+)]i signalling in mammalian (primarily human) sperm, the agonists that may activate these stores and their role in control of sperm function. Finally we consider the evidence that membrane Ca(2)(+) channels and stored Ca(2)(+) may play discrete roles in the regulation of sperm activities and propose a mechanism by which these different components of the sperm Ca(2)(+)-signalling apparatus may interact to generate complex and spatially diverse [Ca(2)(+)]i signals.

Figure 1

(a) Simplified diagrammatic summary of [Ca^{2 +}]_i signalling toolkit in a somatic cell. Ion channels are shown as rectangles with arrow indicating normal direction of Ca^{2 +} flow (yellow, voltage-gated; green, ligand-gated; purple, store-operated; light blue, IP₃ receptor; dark blue, ryanodine receptor; red, NAADP-gated). Pumps are shown as circles with arrows indicating normal direction of Ca^{2 +} movement (red, PMCA'; blue, Na⁺–Ca^{2 +} exchanger; green, SERCA; blue, SPCA). Activation of IP3 receptors by membrane receptor activation and phospholipase C is shown in light blue. Generation of cADPR and NAADP by CD38 and possibly other enzymes (leading to mobilisation of Ca^{2 +} from intracellular stores) is shown by yellow boxes. (b) Structure of human sperm showing positions of CatSper channels (yellow shading around anterior flagellum) and Ca^{2 +} stores in the acrosome and at the sperm neck (redundant nuclear envelope and calreticulin-containing vesicles) (shown in green).

Figure 2

Ca^{2 +} responses evoked in human sperm by uncaging of Ca^{2 +} in the flagellum. Cells were labelled with fluo-4 and loaded with caged Ca^{2 +} (NP-EGTA), then stimulated by an uncaging flash (360 nm laser) at the central flagellum (shown by arrow) while collecting images at 33 Hz. Changes in fluorescence, assessed at each of the positions shown by coloured circles in panel ‘a’, are plotted (normalised to minimum and maximum) in panel ‘b’ using the same colour code. Green, neck; yellow-midpiece; red, proximal flagellum; light blue, mid-distal flagellum; dark blue, distal flagellum.

Figure 3

Model for triggering/regulation of CatSper-activated hyperactivation. CatSper channels in the flagellum (yellow box; shown by yellow shading on sperm flagellum) are activated by diverse stimuli including intracellular pH (pH_i), membrane potential (E _m), progesterone, prostaglandins and other organic molecules. Ca^{2 +} from the flagellum diffuses forward, raising [Ca^{2 +}]_i at the sperm neck and can mobilise stored Ca^{2 +} by Ca^{2 +}-induced Ca^{2 +} release (CICR). Susceptibility of the store to CICR is potentially regulated/sensitised by processes occurring during capacitation, including cAMP signalling, oxidative stress and S-nitrosylation as well as Ca^{2 +} store filling and effects of agonists on Ca^{2 +}-store release channels.