Prostatic acid phosphatase is the main acid phosphatase with 5′-ectonucleotidase activity in the male mouse saliva and regulates salivation

Abstract

Araujo CL, Quintero IB, Kipar A, Herrala AM, Pulkka AE, Saarinen L, Hautaniemi S, Vihko P. Prostatic acid phosphatase is the main acid phosphatase with 5=-ectonucleotidase activity in the male mouse saliva and regulates salivation. Am J Physiol Cell Physiol 306: C1017-C1027, 2014. First published April 9, 2014; doi:10.1152/ajpcell.00062.2014.-We have previously shown that in addition to the well-known secreted isoform of prostatic acid phosphatase (sPAP), a transmembrane isoform exists (TMPAP) that interacts with snapin (a SNARE-associated protein) and regulates the endo-/exocytic pathways. We have also shown that PAP has 5=-ectonucleotidase and thiamine monophosphatase activity and elicits antinociceptive effects in mouse models of chronic inflammatory and neuropathic pain. Therefore, to determine the physiological role of PAP in a typical exocrine organ, we studied the submandibular salivary gland (SMG) of PAP Ϫ/Ϫ and wild-type C57BL/6J mice by microarray analyses, microRNA sequencing, activity tests, immunohistochemistry, and biochemical and physiological analyses of saliva. We show that PAP is the main acid phosphatase in the wild-type male mouse saliva, accounting for 50% of the total acid phosphatase activity, and that it is expressed only in the granular convoluted tubules of the SMGs, where it is the only 5=-ectonucleotidase. The lack of PAP in male PAP Ϫ/Ϫ mice was associated with a significant increase in the salivation volume under secretagogue stimulation, overexpression of genes related to cell proliferation (Mki67, Aurkb, Birc5) and immune response (Irf7, Cxcl9, Ccl3, Fpr2), and upregulation of miR-146a in SMGs. An increased and sustained acinar cell proliferation was detected without signs of glandular hyperplasia. Our results indicate that in PAP Ϫ/Ϫ mice, SMG homeostasis is maintained by an innate immune response. Additionally, we suggest that in male mice, PAP via its 5=-ectonucleotidase activity and production of adenosine can elicit analgesic effects when animals lick their wounds. acid phosphatase; transmembrane prostatic acid phosphatase; 5=-ectonucleotidase activity; TMPase activity; submandibular salivary gland PROSTATIC ACID PHOSPHATASE (PAP, E.C. 3.1.3.2) is a tartratesensitive histidine acid phosphatase enzyme with two known isoforms, the secreted (sPAP) and the type-I transmembrane (TMPAP) isoform, originating from alternative splicing of the same gene (Acpp) (45). Both isoforms are widely expressed in human and mouse tissues. In humans, PAP is predominately expressed in the prostate gland. TMPAP contains an extracellular NH 2 -terminal catalytic domain and a cytosolic COOHterminal domain, carrying a tyrosine-based endosomal/lysosomal targeting motif (Yxx) (45). In addition, TMPAP is an integral membrane protein of cells and is located in the plasma and vesicular membranes, from where it cycles through the endocytic/exocytic pathway via endosomes, multivesicular endosomes, lysosomes, and exosomes (46). Unlike the activity of other acid phosphatases, such as those derived from erythroc...

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