TRPM8 as the rapid testosterone signaling receptor: Implications in the regulation of dimorphic sexual and social behaviors

Adithya Mohandass; Vivek Krishnan; Ekaterina D. Gribkova; Swapna Asuthkar; Padmamalini Baskaran; Yelena Nersesyan; Zahir Hussain; Leslie M. Wise; Robert E. George; Nadarra Stokes; Brenda M. Alexander; Alejandro M. Cohen; Evgeny V. Pavlov; Daniel A. Llano; Michael X. Zhu; Baskaran Thyagarajan; Eleonora Zakharian

doi:10.1096/fj.202000794R

TRPM8 as the rapid testosterone signaling receptor: Implications in the regulation of dimorphic sexual and social behaviors

Adithya Mohandass, Vivek Krishnan, Ekaterina D. Gribkova, Swapna Asuthkar, Padmamalini Baskaran, Yelena Nersesyan, Zahir Hussain, Leslie M. Wise, Robert E. George, Nadarra Stokes, Brenda M. Alexander, Alejandro M. Cohen, Evgeny V. Pavlov, Daniel A. Llano, Michael X. Zhu, Baskaran Thyagarajan, Eleonora Zakharian

Medicine

Research output: Contribution to journal › Article › peer-review

27 Citations (Scopus)

Abstract

Testosterone regulates dimorphic sexual behaviors in all vertebrates. However, the molecular mechanism underlying these behaviors remains unclear. Here, we report that a newly identified rapid testosterone signaling receptor, Transient Receptor Potential Melastatin 8 (TRPM8), regulates dimorphic sexual and social behaviors in mice. We found that, along with higher steroid levels in the circulation, TRPM8^−/− male mice exhibit increased mounting frequency indiscriminate of sex, delayed sexual satiety, and increased aggression compared to wild-type controls, while TRPM8^−/− females display an increased olfaction-exploratory behavior. Furthermore, neuronal responses to acute testosterone application onto the amygdala were attenuated in TRPM8^−/− males but remained unchanged in females. Moreover, activation of dopaminergic neurons in the ventral tegmental area following mating was impaired in TRPM8^−/− males. Together, these results demonstrate that TRPM8 regulates dimorphic sexual and social behaviors, and potentially constitutes a signalosome for mediation of sex-reward mechanism in males. Thus, deficiency of TRPM8 might lead to a delayed sexual satiety phenomenon.

Original language	English
Pages (from-to)	10887-10906
Number of pages	20
Journal	FASEB Journal
Volume	34
Issue number	8
DOIs	https://doi.org/10.1096/fj.202000794R
Publication status	Published - Aug 1 2020

Bibliographical note

Funding Information:
We are grateful to Junling Yang for her immense help with preparation of the brain slices. The research was supported by the National Science Foundation through the grant IOS‐1922428 to EZ; and the National Institutes of Health NIGMS grant award number 1P20GM103432‐01 project 4 to BT.

Publisher Copyright:
© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf Federation of American Societies for Experimental Biology

ASJC Scopus Subject Areas

Biotechnology
Biochemistry
Molecular Biology
Genetics

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Mohandass, A., Krishnan, V., Gribkova, E. D., Asuthkar, S., Baskaran, P., Nersesyan, Y., Hussain, Z., Wise, L. M., George, R. E., Stokes, N., Alexander, B. M., Cohen, A. M., Pavlov, E. V., Llano, D. A., Zhu, M. X., Thyagarajan, B., & Zakharian, E. (2020). TRPM8 as the rapid testosterone signaling receptor: Implications in the regulation of dimorphic sexual and social behaviors. FASEB Journal, 34(8), 10887-10906. https://doi.org/10.1096/fj.202000794R

Mohandass, A, Krishnan, V, Gribkova, ED, Asuthkar, S, Baskaran, P, Nersesyan, Y, Hussain, Z, Wise, LM, George, RE, Stokes, N, Alexander, BM, Cohen, AM, Pavlov, EV, Llano, DA, Zhu, MX, Thyagarajan, B & Zakharian, E 2020, 'TRPM8 as the rapid testosterone signaling receptor: Implications in the regulation of dimorphic sexual and social behaviors', FASEB Journal, vol. 34, no. 8, pp. 10887-10906. https://doi.org/10.1096/fj.202000794R

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title = "TRPM8 as the rapid testosterone signaling receptor: Implications in the regulation of dimorphic sexual and social behaviors",

abstract = "Testosterone regulates dimorphic sexual behaviors in all vertebrates. However, the molecular mechanism underlying these behaviors remains unclear. Here, we report that a newly identified rapid testosterone signaling receptor, Transient Receptor Potential Melastatin 8 (TRPM8), regulates dimorphic sexual and social behaviors in mice. We found that, along with higher steroid levels in the circulation, TRPM8−/− male mice exhibit increased mounting frequency indiscriminate of sex, delayed sexual satiety, and increased aggression compared to wild-type controls, while TRPM8−/− females display an increased olfaction-exploratory behavior. Furthermore, neuronal responses to acute testosterone application onto the amygdala were attenuated in TRPM8−/− males but remained unchanged in females. Moreover, activation of dopaminergic neurons in the ventral tegmental area following mating was impaired in TRPM8−/− males. Together, these results demonstrate that TRPM8 regulates dimorphic sexual and social behaviors, and potentially constitutes a signalosome for mediation of sex-reward mechanism in males. Thus, deficiency of TRPM8 might lead to a delayed sexual satiety phenomenon.",

author = "Adithya Mohandass and Vivek Krishnan and Gribkova, {Ekaterina D.} and Swapna Asuthkar and Padmamalini Baskaran and Yelena Nersesyan and Zahir Hussain and Wise, {Leslie M.} and George, {Robert E.} and Nadarra Stokes and Alexander, {Brenda M.} and Cohen, {Alejandro M.} and Pavlov, {Evgeny V.} and Llano, {Daniel A.} and Zhu, {Michael X.} and Baskaran Thyagarajan and Eleonora Zakharian",

note = "Funding Information: We are grateful to Junling Yang for her immense help with preparation of the brain slices. The research was supported by the National Science Foundation through the grant IOS‐1922428 to EZ; and the National Institutes of Health NIGMS grant award number 1P20GM103432‐01 project 4 to BT. Publisher Copyright: {\textcopyright} 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf Federation of American Societies for Experimental Biology",

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AU - Mohandass, Adithya

AU - Krishnan, Vivek

AU - Gribkova, Ekaterina D.

AU - Asuthkar, Swapna

AU - Baskaran, Padmamalini

AU - Nersesyan, Yelena

AU - Hussain, Zahir

AU - Wise, Leslie M.

AU - George, Robert E.

AU - Stokes, Nadarra

AU - Alexander, Brenda M.

AU - Cohen, Alejandro M.

AU - Pavlov, Evgeny V.

AU - Llano, Daniel A.

AU - Zhu, Michael X.

AU - Thyagarajan, Baskaran

AU - Zakharian, Eleonora

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PY - 2020/8/1

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N2 - Testosterone regulates dimorphic sexual behaviors in all vertebrates. However, the molecular mechanism underlying these behaviors remains unclear. Here, we report that a newly identified rapid testosterone signaling receptor, Transient Receptor Potential Melastatin 8 (TRPM8), regulates dimorphic sexual and social behaviors in mice. We found that, along with higher steroid levels in the circulation, TRPM8−/− male mice exhibit increased mounting frequency indiscriminate of sex, delayed sexual satiety, and increased aggression compared to wild-type controls, while TRPM8−/− females display an increased olfaction-exploratory behavior. Furthermore, neuronal responses to acute testosterone application onto the amygdala were attenuated in TRPM8−/− males but remained unchanged in females. Moreover, activation of dopaminergic neurons in the ventral tegmental area following mating was impaired in TRPM8−/− males. Together, these results demonstrate that TRPM8 regulates dimorphic sexual and social behaviors, and potentially constitutes a signalosome for mediation of sex-reward mechanism in males. Thus, deficiency of TRPM8 might lead to a delayed sexual satiety phenomenon.

AB - Testosterone regulates dimorphic sexual behaviors in all vertebrates. However, the molecular mechanism underlying these behaviors remains unclear. Here, we report that a newly identified rapid testosterone signaling receptor, Transient Receptor Potential Melastatin 8 (TRPM8), regulates dimorphic sexual and social behaviors in mice. We found that, along with higher steroid levels in the circulation, TRPM8−/− male mice exhibit increased mounting frequency indiscriminate of sex, delayed sexual satiety, and increased aggression compared to wild-type controls, while TRPM8−/− females display an increased olfaction-exploratory behavior. Furthermore, neuronal responses to acute testosterone application onto the amygdala were attenuated in TRPM8−/− males but remained unchanged in females. Moreover, activation of dopaminergic neurons in the ventral tegmental area following mating was impaired in TRPM8−/− males. Together, these results demonstrate that TRPM8 regulates dimorphic sexual and social behaviors, and potentially constitutes a signalosome for mediation of sex-reward mechanism in males. Thus, deficiency of TRPM8 might lead to a delayed sexual satiety phenomenon.

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TRPM8 as the rapid testosterone signaling receptor: Implications in the regulation of dimorphic sexual and social behaviors

Abstract

Bibliographical note

ASJC Scopus Subject Areas

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