Every year, more than 5 million people die primarily from developing smoking related lung cancer. Tobacco contains nicotine, the major compound responsible for driving the strong addiction to smoking. Nicotine is addictive because of its effects on the central nervous system mediated by nicotinic acetylcholine receptors (nAChRs). The ability to sense the bitter taste of phenylthiocarbamide due to polymorphisms in a taste receptor gene (T2R38) protects a subject from developing a cigarette smoking addiction and reduces the positive reinforcement from smoking. This suggests that changes in taste play a significant role in the context of cigarette smoking and provide important cues involved in nicotine addiction. Although nicotine is described as bitter tasting, the molecular and cellular mechanisms that encode the taste of nicotine remain unclear. Our studies show that nicotine activates the taste system via two parallel receptor-mediated pathways. One pathway involves a G-protein coupled receptor (T2R) and down stream effectors (a G-protein gustducin, an enzyme PLC?2 and a cation channel, TRPM5) that are common to sweet, bitter and umami bitter sensing. The second pathway utilizes nAChRs and responds to nicotine, acetylcholine, ethanol and perhaps other bitter tastants and is essential for their complete sensory representation. The overall aim of this study is to increase our understanding of the contribution of different nAChR subunits to the bitter taste of nicotine, acetylcholine, ethanol and other bitter compounds. Studies are designed to investigate the presence of different nAChR subunits in taste bud cells using molecular techniques (RT-PCR, quantitative-RT-PCT, immunohistochemical and in situ hybridization). To investigate the role of nAChRs in peripheral taste transduction we will monitor the effects of pharmacological agonists and antagonists of nAChRs on single isolated taste cells using whole cell patch clamp technique, chorda tympani taste nerve responses and on lick rates as a measure of altered behavioral responses to nicotine, acetylcholine, ethanol and other bitter tastants in several animal models. Specifically, we will use genetically modified mice in which specific nAChR subunit genes or genes for TRPM5 cation channel have been deleted. The information obtained in this study on the nAChR-dependent bitter- sensing pathway may provide us with information regarding taste-related events that may be either involved in or predictors of nicotine and alcohol addiction. The effects of cigarette smoking on food consumption and taste preferences may occur from peripheral taste modulation due to chronic exposure to nicotine acting on nAChRs in taste buds among other factors.

Public Health Relevance

Alterations in taste play a significant role in the context of cigarette smoking and alcohol abuse and provide important cues involved in their addiction. Therefore, it is important to understand the molecular and cellular mechanisms that encode the bitter taste of nicotine and ethanol. Our studies indicate that nicotinic acetylcholine receptors provide another bitter sensing mechanism that works in parallel with the TRPM5- dependent transduction pathway and is necessary for the complete representation of the bitter taste of nicotine, ethanol and perhaps other bitter tastants.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
1R01DC011569-01A1
Application #
8295798
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sullivan, Susan L
Project Start
2012-07-01
Project End
2017-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$313,059
Indirect Cost
$96,498
Name
Virginia Commonwealth University
Department
Physiology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Qian, Jie; Mummalaneni, Shobha; Grider, John R et al. (2018) Nicotinic acetylcholine receptors (nAChRs) are expressed in Trpm5 positive taste receptor cells (TRCs). PLoS One 13:e0190465
Qian, Jie; Mummalaneni, Shobha; Phan, Tam-Hao T et al. (2017) Cyclic-AMP regulates postnatal development of neural and behavioral responses to NaCl in rats. PLoS One 12:e0171335
Qian, Jie; Mummalaneni, Shobha K; Alkahtani, Reem M et al. (2016) Nicotine-Induced Effects on Nicotinic Acetylcholine Receptors (nAChRs), Ca2+ and Brain-Derived Neurotrophic Factor (BDNF) in STC-1 Cells. PLoS One 11:e0166565
Ren, Zuo Jun; Mummalaneni, Shobha; Qian, Jie et al. (2015) Nicotinic Acetylcholine Receptor (nAChR) Dependent Chorda Tympani Taste Nerve Responses to Nicotine, Ethanol and Acetylcholine. PLoS One 10:e0127936
DeSimone, John A; Phan, Tam-Hao T; Mummalaneni, Shobha et al. (2015) Regulatory Effects of Ca2+ and H+ on the Rat Chorda Tympani Response to NaCl and KCl. Chem Senses 40:401-12
Mummalaneni, Shobha; Qian, Jie; Phan, Tam-Hao T et al. (2014) Effect of ENaC modulators on rat neural responses to NaCl. PLoS One 9:e98049
Kim, Min Jung; Son, Hee Jin; Kim, Yiseul et al. (2014) Selective activation of hTRPV1 by N-geranyl cyclopropylcarboxamide, an amiloride-insensitive salt taste enhancer. PLoS One 9:e89062
Kendig, Derek M; Hurst, Norman R; Bradley, Zachary L et al. (2014) Activation of the umami taste receptor (T1R1/T1R3) initiates the peristaltic reflex and pellet propulsion in the distal colon. Am J Physiol Gastrointest Liver Physiol 307:G1100-7
Zha, Beth S; Wan, Xiaoshan; Zhang, Xiaoxuan et al. (2013) HIV protease inhibitors disrupt lipid metabolism by activating endoplasmic reticulum stress and inhibiting autophagy activity in adipocytes. PLoS One 8:e59514
Ren, ZuoJun; Rhyu, Mee-Ra; Phan, Tam-Hao T et al. (2013) TRPM5-dependent amiloride- and benzamil-insensitive NaCl chorda tympani taste nerve response. Am J Physiol Gastrointest Liver Physiol 305:G106-17

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