M3 muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice

Takeshi Nakamura, Minoru Matsui, Keiko Uchida, Akira Futatsugi, Shinji Kusakawa, Nagisa Matsumoto, Kyoko Nakamura, Toshiya Manabe, Makoto M. Taketo, Katsuhiko Mikoshiba

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

The M1 and M3 subtypes are the major muscarinic acetylcholine receptors in the salivary gland and M3 is reported to be more abundant. However, despite initial reports of salivation abnormalities in M3-knockout (M3KO) mice, it is still unclear which subtype is functionally relevant in physiological salivation. In the present study, salivary secretory function was examined using mice lacking specific subtype(s) of muscarinic receptor. The carbachol-induced [Ca2+]i increase was markedly impaired in submandibular gland cells from M3KO mice and completely absent in those from M1/M3KO mice. This demonstrates that M3 and M1 play major and minor roles, respectively, in the cholinergically induced [Ca2+]i increase. Two-dimensional Ca2+-imaging analysis revealed the patchy distribution of M1 in submandibular gland acini, in contrast to the ubiquitous distribution of M3. In vivo administration of a high dose of pilocarpine (10 mg kg-1, s.c.) to M3KO mice caused salivation comparable to that in wild-type mice, while no salivation was induced in M1/M3KO mice, indicating that salivation in M3KO mice is caused by an M1-mediated [Ca2+]i increase. In contrast, a lower dose of pilocarpine (1 mg kg-1, s.c.) failed to induce salivation in M3KO mice, but induced abundant salivation in wild-type mice, indicating that M3-mediated salivation has a lower threshold than M1-mediated salivation. In addition, M3KO mice, but not M1KO mice, had difficulty in eating dry food, as shown by frequent drinking during feeding, suggesting that salivation during eating is mediated by M3 and that M1 plays no practical role in it. These results show that the M3 subtype is essential for parasympathetic control of salivation and a reasonable target for the drug treatment and gene therapy of xerostomia, including Sjögren's syndrome.

Original languageEnglish
Pages (from-to)561-575
Number of pages15
JournalJournal of Physiology
Volume558
Issue number2
DOIs
Publication statusPublished - 2004 Jul 15
Externally publishedYes

Fingerprint

Salivation
Muscarinic Receptors
Knockout Mice
Pilocarpine
Submandibular Gland
Eating
Xerostomia
Carbachol
Salivary Glands
Genetic Therapy
Drinking

ASJC Scopus subject areas

  • Physiology

Cite this

M3 muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice. / Nakamura, Takeshi; Matsui, Minoru; Uchida, Keiko; Futatsugi, Akira; Kusakawa, Shinji; Matsumoto, Nagisa; Nakamura, Kyoko; Manabe, Toshiya; Taketo, Makoto M.; Mikoshiba, Katsuhiko.

In: Journal of Physiology, Vol. 558, No. 2, 15.07.2004, p. 561-575.

Research output: Contribution to journalArticle

Nakamura, T, Matsui, M, Uchida, K, Futatsugi, A, Kusakawa, S, Matsumoto, N, Nakamura, K, Manabe, T, Taketo, MM & Mikoshiba, K 2004, 'M3 muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice', Journal of Physiology, vol. 558, no. 2, pp. 561-575. https://doi.org/10.1113/jphysiol.2004.064626
Nakamura, Takeshi ; Matsui, Minoru ; Uchida, Keiko ; Futatsugi, Akira ; Kusakawa, Shinji ; Matsumoto, Nagisa ; Nakamura, Kyoko ; Manabe, Toshiya ; Taketo, Makoto M. ; Mikoshiba, Katsuhiko. / M3 muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice. In: Journal of Physiology. 2004 ; Vol. 558, No. 2. pp. 561-575.
@article{7bf62d6bcdcc4ee9bdc59969e26c5879,
title = "M3 muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice",
abstract = "The M1 and M3 subtypes are the major muscarinic acetylcholine receptors in the salivary gland and M3 is reported to be more abundant. However, despite initial reports of salivation abnormalities in M3-knockout (M3KO) mice, it is still unclear which subtype is functionally relevant in physiological salivation. In the present study, salivary secretory function was examined using mice lacking specific subtype(s) of muscarinic receptor. The carbachol-induced [Ca2+]i increase was markedly impaired in submandibular gland cells from M3KO mice and completely absent in those from M1/M3KO mice. This demonstrates that M3 and M1 play major and minor roles, respectively, in the cholinergically induced [Ca2+]i increase. Two-dimensional Ca2+-imaging analysis revealed the patchy distribution of M1 in submandibular gland acini, in contrast to the ubiquitous distribution of M3. In vivo administration of a high dose of pilocarpine (10 mg kg-1, s.c.) to M3KO mice caused salivation comparable to that in wild-type mice, while no salivation was induced in M1/M3KO mice, indicating that salivation in M3KO mice is caused by an M1-mediated [Ca2+]i increase. In contrast, a lower dose of pilocarpine (1 mg kg-1, s.c.) failed to induce salivation in M3KO mice, but induced abundant salivation in wild-type mice, indicating that M3-mediated salivation has a lower threshold than M1-mediated salivation. In addition, M3KO mice, but not M1KO mice, had difficulty in eating dry food, as shown by frequent drinking during feeding, suggesting that salivation during eating is mediated by M3 and that M1 plays no practical role in it. These results show that the M3 subtype is essential for parasympathetic control of salivation and a reasonable target for the drug treatment and gene therapy of xerostomia, including Sj{\"o}gren's syndrome.",
author = "Takeshi Nakamura and Minoru Matsui and Keiko Uchida and Akira Futatsugi and Shinji Kusakawa and Nagisa Matsumoto and Kyoko Nakamura and Toshiya Manabe and Taketo, {Makoto M.} and Katsuhiko Mikoshiba",
year = "2004",
month = "7",
day = "15",
doi = "10.1113/jphysiol.2004.064626",
language = "English",
volume = "558",
pages = "561--575",
journal = "Journal of Physiology",
issn = "0022-3751",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - M3 muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice

AU - Nakamura, Takeshi

AU - Matsui, Minoru

AU - Uchida, Keiko

AU - Futatsugi, Akira

AU - Kusakawa, Shinji

AU - Matsumoto, Nagisa

AU - Nakamura, Kyoko

AU - Manabe, Toshiya

AU - Taketo, Makoto M.

AU - Mikoshiba, Katsuhiko

PY - 2004/7/15

Y1 - 2004/7/15

N2 - The M1 and M3 subtypes are the major muscarinic acetylcholine receptors in the salivary gland and M3 is reported to be more abundant. However, despite initial reports of salivation abnormalities in M3-knockout (M3KO) mice, it is still unclear which subtype is functionally relevant in physiological salivation. In the present study, salivary secretory function was examined using mice lacking specific subtype(s) of muscarinic receptor. The carbachol-induced [Ca2+]i increase was markedly impaired in submandibular gland cells from M3KO mice and completely absent in those from M1/M3KO mice. This demonstrates that M3 and M1 play major and minor roles, respectively, in the cholinergically induced [Ca2+]i increase. Two-dimensional Ca2+-imaging analysis revealed the patchy distribution of M1 in submandibular gland acini, in contrast to the ubiquitous distribution of M3. In vivo administration of a high dose of pilocarpine (10 mg kg-1, s.c.) to M3KO mice caused salivation comparable to that in wild-type mice, while no salivation was induced in M1/M3KO mice, indicating that salivation in M3KO mice is caused by an M1-mediated [Ca2+]i increase. In contrast, a lower dose of pilocarpine (1 mg kg-1, s.c.) failed to induce salivation in M3KO mice, but induced abundant salivation in wild-type mice, indicating that M3-mediated salivation has a lower threshold than M1-mediated salivation. In addition, M3KO mice, but not M1KO mice, had difficulty in eating dry food, as shown by frequent drinking during feeding, suggesting that salivation during eating is mediated by M3 and that M1 plays no practical role in it. These results show that the M3 subtype is essential for parasympathetic control of salivation and a reasonable target for the drug treatment and gene therapy of xerostomia, including Sjögren's syndrome.

AB - The M1 and M3 subtypes are the major muscarinic acetylcholine receptors in the salivary gland and M3 is reported to be more abundant. However, despite initial reports of salivation abnormalities in M3-knockout (M3KO) mice, it is still unclear which subtype is functionally relevant in physiological salivation. In the present study, salivary secretory function was examined using mice lacking specific subtype(s) of muscarinic receptor. The carbachol-induced [Ca2+]i increase was markedly impaired in submandibular gland cells from M3KO mice and completely absent in those from M1/M3KO mice. This demonstrates that M3 and M1 play major and minor roles, respectively, in the cholinergically induced [Ca2+]i increase. Two-dimensional Ca2+-imaging analysis revealed the patchy distribution of M1 in submandibular gland acini, in contrast to the ubiquitous distribution of M3. In vivo administration of a high dose of pilocarpine (10 mg kg-1, s.c.) to M3KO mice caused salivation comparable to that in wild-type mice, while no salivation was induced in M1/M3KO mice, indicating that salivation in M3KO mice is caused by an M1-mediated [Ca2+]i increase. In contrast, a lower dose of pilocarpine (1 mg kg-1, s.c.) failed to induce salivation in M3KO mice, but induced abundant salivation in wild-type mice, indicating that M3-mediated salivation has a lower threshold than M1-mediated salivation. In addition, M3KO mice, but not M1KO mice, had difficulty in eating dry food, as shown by frequent drinking during feeding, suggesting that salivation during eating is mediated by M3 and that M1 plays no practical role in it. These results show that the M3 subtype is essential for parasympathetic control of salivation and a reasonable target for the drug treatment and gene therapy of xerostomia, including Sjögren's syndrome.

UR - http://www.scopus.com/inward/record.url?scp=4344605231&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=4344605231&partnerID=8YFLogxK

U2 - 10.1113/jphysiol.2004.064626

DO - 10.1113/jphysiol.2004.064626

M3 - Article

C2 - 15146045

AN - SCOPUS:4344605231

VL - 558

SP - 561

EP - 575

JO - Journal of Physiology

JF - Journal of Physiology

SN - 0022-3751

IS - 2

ER -