Calcium regulation of the soluble adenylyl cyclase expressed in mammalian spermatozoa

Jaiswal, Bijay S.; Conti, Marco

doi:10.1073/pnas.1831008100

Cited by 233 publications

(216 citation statements)

References 67 publications

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“…One mechanism by which calcium is directly linked to flagellar function is through its regulation of the atypical 'soluble' adenylyl cyclase (sAC), which generates cAMP to activate PKA. The sAC is required for sperm motility and is molecularly and biochemically distinct from the transmembrane adenylyl cyclases (tmACs), in part because sAC is uniquely sensitive to both bicarbonate and calcium (Buck et al 1999;Chen et al 2000;Wuttke et al 2001;Jaiswal and Conti 2003;Litvin et al 2003;Esposito et al 2004;Liguori et al 2004;Hess et al 2005). Thus, through sAC, calcium signalling can be linked to PKA signalling as parts of a single pathway.…”

Section: Calcium Signallingmentioning

confidence: 99%

Moving to the beat: a review of mammalian sperm motility regulation

Turner¹

2006

Reprod. Fertil. Dev.

248

184

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Abstract. Because it is generally accepted that a high percentage of poorly motile or immotile sperm will adversely affect male fertility, analysis of sperm motility is a central part of the evaluation of male fertility. In spite of its importance to fertility, poor sperm motility remains only a description of a pathology whose underlying cause is typically poorly understood. The present review is designed to bring the clinician up to date with the most current understanding of the mechanisms that regulate sperm motility and to raise questions about how aberrations in these mechanisms could be the underlying causes of this pathology.

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Section: Calcium Signallingmentioning

confidence: 99%

Moving to the beat: a review of mammalian sperm motility regulation

Turner¹

2006

Reprod. Fertil. Dev.

248

184

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“…Previously, calcium had been identified as an activator of sAC (20,21,28,41). On the other hand, calcium is also known to regulate several types of tmACs, some of which are expressed in PC12 cells (31).…”

Section: Ngf Signals Via Calcium To Raise Intracellular Camp and Actimentioning

confidence: 99%

“…We have identified an additional, ubiquitously expressed (17,18) source of cAMP in mammalian cells, "soluble" adenylyl cyclase (sAC) (16). In contrast to tmACs, sAC is not regulated by heterotrimeric G proteins but is, instead, regulated by bicarbonate (19) and calcium (20,21) ions. Also, in contrast to tmACs, sAC is not bound to the plasma membrane but is localized to various intracellular compartments (22), where it is thought to be the source of local pools of cAMP (23,24).…”

mentioning

confidence: 99%

Soluble Adenylyl Cyclase Mediates Nerve Growth Factor-induced Activation of Rap1

Stessin

Zippin

Kamenetsky³

et al. 2006

Journal of Biological Chemistry

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Nerve growth factor (NGF) and the ubiquitous second messenger cyclic AMP (cAMP) are both implicated in neuronal differentiation. Multiple studies indicate that NGF signals to at least a subset of its targets via cAMP, but the link between NGF and cAMP has remained elusive. Here, we have described the use of small molecule inhibitors to differentiate between the two known sources of cAMP in mammalian cells, bicarbonate-and calcium-responsive soluble adenylyl cyclase (sAC) and G protein-regulated transmembrane adenylyl cyclases. These inhibitors, along with sAC-specific small interfering RNA, reveal that sAC is uniquely responsible for the NGF-elicited rise in cAMP and is essential for the NGF-induced activation of the small G protein Rap1 in PC12 cells. In contrast and as expected, transmembrane adenylyl cyclase-generated cAMP is responsible for Rap1 activation by the G protein-coupled receptor ligand PACAP (pituitary adenylyl cyclase-activating peptide). These results identify sAC as a mediator of NGF signaling and reveal the existence of distinct pathways leading to cAMP-dependent signal transduction.

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“…In addition to its bicarbonate sensitivity, sAC is synergistically activated by calcium 10 , and this potentiation seems to be important for sperm maturation 11 .…”

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confidence: 99%

Bicarbonate activation of adenylyl cyclase via promotion of catalytic active site closure and metal recruitment

Steegborn

Litvin

Levin

et al. 2004

Nat Struct Mol Biol

154

240

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In an evolutionarily conserved signaling pathway, 'soluble' adenylyl cyclases (sACs) synthesize the ubiquitous second messenger cyclic adenosine 3′,5′-monophosphate (cAMP) in response to bicarbonate and calcium signals. Here, we present crystal structures of a cyanobacterial sAC enzyme in complex with ATP analogs, calcium and bicarbonate, which represent distinct catalytic states of the enzyme. The structures reveal that calcium occupies the first ion-binding site and directly mediates nucleotide binding. The single ion-occupied, nucleotide-bound state defines a novel, open adenylyl cyclase state. In contrast, bicarbonate increases the catalytic rate by inducing marked active site closure and recruiting a second, catalytic ion. The phosphates of the bound substrate analogs are rearranged, which would facilitate product formation and release. The mechanisms of calcium and bicarbonate sensing define a reaction pathway involving active site closure and metal recruitment that may be universal for class III cyclases.The ubiquitous second messenger cAMP regulates a large variety of essential physiological processes such as gene expression, chromosome segregation and cellular metabolism. In mammalian cells, cAMP is synthesized by a family of nine transmembrane adenylyl cyclases (tmACs) and one sAC 1 . Unlike tmACs, which localize to the cellular membrane and respond to extracellular stimuli via heterotrimeric G proteins 1 , sAC is found in various intracellular compartments such as the mitochondria and the nucleus 2 . Its localization near intracellular cAMP targets is the impetus for current models of second messenger signal transduction, in which cAMP functions as a locally acting signaling molecule 2-4 .sAC is insensitive to the tmAC regulators calmodulin and heterotrimeric G proteins as well as the nonphysiological activator forskolin; instead, sAC senses physiological levels of bicarbonate 5 . Aside from its role as a universal physiological buffer maintaining cellular and extracellular pH, bicarbonate functions as a signaling molecule 3 , regulating many biological processes in mammals such as fertility 6 , acid-base homeostasis, breathing rate, metabolism and fluid transport (reviewed in ref. 7). As the only known signaling enzyme sensitive to physiological fluctuations of bicarbonate 5 , sAC probably mediates each of these processes. Bicarbonate activation of sAC is essential for sperm motility 8 as well as for pH-dependent COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. acid secretion in the epididymis and possibly the kidney 9 . In addition to its bicarbonate sensitivity, sAC is synergistically activated by calcium 10 , and this potentiation seems to be important for sperm maturation 11 . NIH Public AccessPrevious work has revealed the overall structure of tmAC enzymes and suggested a twometal ion mechanism for catalysis 12,13 . Despite their different regulation, mammalian sAC and tmACs are grouped into the nucleotidyl cyclase class III based on sequ...

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Calcium regulation of the soluble adenylyl cyclase expressed in mammalian spermatozoa

Cited by 233 publications

References 67 publications

Moving to the beat: a review of mammalian sperm motility regulation

Moving to the beat: a review of mammalian sperm motility regulation

Soluble Adenylyl Cyclase Mediates Nerve Growth Factor-induced Activation of Rap1

Bicarbonate activation of adenylyl cyclase via promotion of catalytic active site closure and metal recruitment

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