Lysine 101 in the CRAC Motif in Transmembrane Helix 2 Confers Cholesterol-Induced Thermal Stability to the Serotonin1A Receptor

Sarkar, Parijat; Bhat, Akrati; Chattopadhyay, Amitabha

doi:10.1007/s00232-022-00262-w

Cited by 5 publications

(4 citation statements)

References 77 publications

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“…In some cases, CHS has been used to substitute cholesterol in GPCRs, although the validity of this replacement has been contested [ 93 , 123 , 124 , 125 ]. The CRAC motif has been established as a characteristic feature of the serotonin (1A) receptor [ 126 ], the

2-adrenergic receptor [ 127 ], cholecystokinin [ 121 ], cannabinoid (CB1) receptor [ 128 ], etc. [ 92 , 93 , 129 ], indicating that the interaction of cholesterol with GPCRs could be specific in nature.…”

Section: Introductionmentioning

confidence: 99%

Cholesterol in Class C GPCRs: Role, Relevance, and Localization

et al. 2023

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G-protein coupled receptors (GPCRs), one of the largest superfamilies of cell-surface receptors, are heptahelical integral membrane proteins that play critical roles in virtually every organ system. G-protein-coupled receptors operate in membranes rich in cholesterol, with an imbalance in cholesterol level within the vicinity of GPCR transmembrane domains affecting the structure and/or function of many GPCRs, a phenomenon that has been linked to several diseases. These effects of cholesterol could result in indirect changes by altering the mechanical properties of the lipid environment or direct changes by binding to specific sites on the protein. There are a number of studies and reviews on how cholesterol modulates class A GPCRs; however, this area of study is yet to be explored for class C GPCRs, which are characterized by a large extracellular region and often form constitutive dimers. This review highlights specific sites of interaction, functions, and structural dynamics involved in the cholesterol recognition of the class C GPCRs. We summarize recent data from some typical family members to explain the effects of membrane cholesterol on the structural features and functions of class C GPCRs and speculate on their corresponding therapeutic potential.

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Section: Introductionmentioning

confidence: 99%

Cholesterol in Class C GPCRs: Role, Relevance, and Localization

et al. 2023

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“…Furthermore, the lysine K101 residue in the CRAC motif of the cholesterol’s transmembrane helix plays a vital role in safeguarding 5-HT 1A -Rs from thermal deactivation. Any mutation in this residue leads to the loss of 5-HT 1A -Rs’ thermal stability, a condition independent of membrane cholesterol content . Several studies suggest a direct interaction between cholesterol and 5-HT-Rs impacts receptor functioning.…”

Section: Lipid Regulation Of the 5-ht Synapsementioning

confidence: 99%

“…Any mutation in this residue leads to the loss of 5-HT 1A -Rs' thermal stability, a condition independent of membrane cholesterol content. 174 Several studies suggest a direct interaction between cholesterol and 5-HT-Rs impacts receptor functioning. A decrease in membrane cholesterol levels due to the specific inhibitor methyl-β-cyclodextrin (MβCD), or the solubilization of native hippocampal membranes, results in reduced binding of receptor antagonists and agonists to the 5-HT 1A -Rs in hippocampal cell culture.…”

Section: ■ Introductionmentioning

confidence: 99%

Serotonin Signaling through Lipid Membranes

Kalinichenko,

Kornhuber,

Sinning

et al. 2024

ACS Chem. Neurosci.

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Serotonin (5-HT) is a vital modulatory neurotransmitter responsible for regulating most behaviors in the brain. An inefficient 5-HT synaptic function is often linked to various mental disorders. Primarily, membrane proteins controlling the expression and activity of 5-HT synthesis, storage, release, receptor activation, and inactivation are critical to 5-HT signaling in synaptic and extra-synaptic sites. Moreover, these signals represent information transmission across membranes. Although the lipid membrane environment is often viewed as fairly stable, emerging research suggests significant functional lipid−protein interactions with many synaptic 5-HT proteins. These protein−lipid interactions extend to almost all the primary lipid classes that form the plasma membrane. Collectively, these lipid classes and lipid−protein interactions affect 5-HT synaptic efficacy at the synapse. The highly dynamic lipid composition of synaptic membranes suggests that these lipids and their interactions with proteins may contribute to the plasticity of the 5-HT synapse. Therefore, this broader protein−lipid model of the 5-HT synapse necessitates a reconsideration of 5-HT's role in various associated mental disorders.

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“…SMO is a member of the GPCR family of receptors, one of the most studied classes of membrane receptors involved in signal transduction across the plasma membrane ( Katritch et al, 2013 ; Chattopadhyay, 2014 ; Sakmar, 2017 ). Although the role of cholesterol in mediating a varied aspects of GPCR function such as signaling, stability, oligomerization, endocytosis and trafficking constitutes an exciting contemporary area of research ( Pucadyil and Chattopadhyay, 2006 ; Paila and Chattopadhyay, 2010 ; Oates and Watts, 2011 ; Goddard and Watts, 2012 ; Chattopadhyay, 2014 ; Sengupta and Chattopadhyay, 2015 ; Gimpl, 2016 ; Sengupta et al, 2018 ; Jafurulla et al, 2019 ; Kiriakidi et al, 2019 ; Sarkar et al, 2020 ; Jakubík and El-Fakahany, 2021 ; Kumar and Chattopadhyay, 2021a ; Sarkar et al, 2022 ; Sarkar and Chattopadhyay, 2022 ), activation of SMO by cholesterol has recently added a new functional dimension to this area of work ( Luchetti et al, 2016 ; Kinnebrew et al, 2022 ; Kumari et al, 2022 ).…”

Section: Defective Hedgehog Signaling In Slosmentioning

confidence: 99%

Smith-Lemli-Opitz syndrome: A pathophysiological manifestation of the Bloch hypothesis

Chattopadhyay

Sharma²

2023

Front. Mol. Biosci.

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The biosynthesis of cholesterol, an essential component of higher eukaryotic membranes, was worked out by Konrad Bloch (and Feodor Lynen) in the 1960s and they received the Nobel Prize around that time in recognition of their pioneering contributions. An elegant consequence of this was a hypothesis proposed by Konrad Bloch (the Bloch hypothesis) which suggests that each subsequent intermediate in the cholesterol biosynthesis pathway is superior in supporting membrane function in higher eukaryotes relative to its precursor. In this review, we discuss an autosomal recessive metabolic disorder, known as Smith-Lemli-Opitz syndrome (SLOS), associated with a defect in the Kandutsch-Russell pathway of cholesterol biosynthesis that results in accumulation of the immediate precursor of cholesterol in its biosynthetic pathway (7-dehydrocholesterol) and an altered cholesterol to total sterol ratio. Patients suffering from SLOS have several developmental, behavioral and cognitive abnormalities for which no drug is available yet. We characterize SLOS as a manifestation of the Bloch hypothesis and review its molecular etiology and current treatment. We further discuss defective Hedgehog signaling in SLOS and focus on the role of the serotonin1A receptor, a representative neurotransmitter receptor belonging to the GPCR family, in SLOS. Notably, ligand binding activity and cellular signaling of serotonin1A receptors are impaired in SLOS-like condition. Importantly, cellular localization and intracellular trafficking of the serotonin1A receptor (which constitute an important determinant of a GPCR cellular function) are compromised in SLOS. We highlight some of the recent developments and emerging concepts in SLOS pathobiology and suggest that novel therapies based on trafficking defects of target receptors could provide new insight into treatment of SLOS.

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Lysine 101 in the CRAC Motif in Transmembrane Helix 2 Confers Cholesterol-Induced Thermal Stability to the Serotonin1A Receptor

Cited by 5 publications

References 77 publications

Cholesterol in Class C GPCRs: Role, Relevance, and Localization

Cholesterol in Class C GPCRs: Role, Relevance, and Localization

Serotonin Signaling through Lipid Membranes

Smith-Lemli-Opitz syndrome: A pathophysiological manifestation of the Bloch hypothesis

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