statin impairs the function and dynamics of Human Serotonin 1A Receptors

[Guest guest]

Chronic cholesterol depletion using statin impairs the function and dynamics of

Human Serotonin 1A Receptors

Sandeep Shrivastava, J. Pucadyil‡, Yamuna Devi Paila, Sourav Ganguly and

Amitabha Chattopadhyay*

Centre for Cellular and Molecular Biology, Council of Scientific and Industrial

Research, Uppal Road, Hyderabad 500 007, India

Biochemistry, 2010, 49 (26), pp 5426–5435

DOI: 10.1021/bi100276b

Publication Date (Web): June 3, 2010

American Chemical Society

Statins are potent inhibitors of HMG-CoA reductase, the key rate-limiting enzyme

in cholesterol biosynthesis, and are some of the best selling drugs globally. We

have explored the effect of chronic cholesterol depletion induced by mevastatin

on the function of human serotonin1A receptors expressed in CHO cells. An

advantage with statins is that cholesterol depletion is chronic which mimics

physiological conditions. Our results show a significant reduction in the level

of specific ligand binding and G-protein coupling to serotonin1A receptors upon

chronic cholesterol depletion, although the membrane receptor level is not

reduced at all. Interestingly, replenishment of mevastatin-treated cells with

cholesterol resulted in the recovery of specific ligand binding and G-protein

coupling. Treatment of cells expressing serotonin1A receptors with mevastatin

led to a decrease in the diffusion coefficient and an increase in the mobile

fraction of the receptor, as determined by fluorescence recovery after

photobleaching measurements. To the best of our knowledge, these results

constitute the first report describing the effect of chronic cholesterol

depletion on the organization and function of a G-protein-coupled neuronal

receptor. Our results assume significance in view of recent reports highlighting

the symptoms of anxiety and depression in humans upon statin administration, and

the role of serotonin1A receptors in anxiety and depression.

[Guest guest]

Chronic cholesterol depletion using statin impairs the function and dynamics of

Human Serotonin 1A Receptors

Sandeep Shrivastava, J. Pucadyil‡, Yamuna Devi Paila, Sourav Ganguly and

Amitabha Chattopadhyay*

Centre for Cellular and Molecular Biology, Council of Scientific and Industrial

Research, Uppal Road, Hyderabad 500 007, India

Biochemistry, 2010, 49 (26), pp 5426–5435

DOI: 10.1021/bi100276b

Publication Date (Web): June 3, 2010

American Chemical Society

Statins are potent inhibitors of HMG-CoA reductase, the key rate-limiting enzyme

in cholesterol biosynthesis, and are some of the best selling drugs globally. We

have explored the effect of chronic cholesterol depletion induced by mevastatin

on the function of human serotonin1A receptors expressed in CHO cells. An

advantage with statins is that cholesterol depletion is chronic which mimics

physiological conditions. Our results show a significant reduction in the level

of specific ligand binding and G-protein coupling to serotonin1A receptors upon

chronic cholesterol depletion, although the membrane receptor level is not

reduced at all. Interestingly, replenishment of mevastatin-treated cells with

cholesterol resulted in the recovery of specific ligand binding and G-protein

coupling. Treatment of cells expressing serotonin1A receptors with mevastatin

led to a decrease in the diffusion coefficient and an increase in the mobile

fraction of the receptor, as determined by fluorescence recovery after

photobleaching measurements. To the best of our knowledge, these results

constitute the first report describing the effect of chronic cholesterol

depletion on the organization and function of a G-protein-coupled neuronal

receptor. Our results assume significance in view of recent reports highlighting

the symptoms of anxiety and depression in humans upon statin administration, and

the role of serotonin1A receptors in anxiety and depression.

[Guest guest]

Chronic cholesterol depletion using statin impairs the function and dynamics of

Human Serotonin 1A Receptors

Sandeep Shrivastava, J. Pucadyil‡, Yamuna Devi Paila, Sourav Ganguly and

Amitabha Chattopadhyay*

Centre for Cellular and Molecular Biology, Council of Scientific and Industrial

Research, Uppal Road, Hyderabad 500 007, India

Biochemistry, 2010, 49 (26), pp 5426–5435

DOI: 10.1021/bi100276b

Publication Date (Web): June 3, 2010

American Chemical Society

Statins are potent inhibitors of HMG-CoA reductase, the key rate-limiting enzyme

in cholesterol biosynthesis, and are some of the best selling drugs globally. We

have explored the effect of chronic cholesterol depletion induced by mevastatin

on the function of human serotonin1A receptors expressed in CHO cells. An

advantage with statins is that cholesterol depletion is chronic which mimics

physiological conditions. Our results show a significant reduction in the level

of specific ligand binding and G-protein coupling to serotonin1A receptors upon

chronic cholesterol depletion, although the membrane receptor level is not

reduced at all. Interestingly, replenishment of mevastatin-treated cells with

cholesterol resulted in the recovery of specific ligand binding and G-protein

coupling. Treatment of cells expressing serotonin1A receptors with mevastatin

led to a decrease in the diffusion coefficient and an increase in the mobile

fraction of the receptor, as determined by fluorescence recovery after

photobleaching measurements. To the best of our knowledge, these results

constitute the first report describing the effect of chronic cholesterol

depletion on the organization and function of a G-protein-coupled neuronal

receptor. Our results assume significance in view of recent reports highlighting

the symptoms of anxiety and depression in humans upon statin administration, and

the role of serotonin1A receptors in anxiety and depression.

[Guest guest]

Chronic cholesterol depletion using statin impairs the function and dynamics of

Human Serotonin 1A Receptors

Sandeep Shrivastava, J. Pucadyil‡, Yamuna Devi Paila, Sourav Ganguly and

Amitabha Chattopadhyay*

Centre for Cellular and Molecular Biology, Council of Scientific and Industrial

Research, Uppal Road, Hyderabad 500 007, India

Biochemistry, 2010, 49 (26), pp 5426–5435

DOI: 10.1021/bi100276b

Publication Date (Web): June 3, 2010

American Chemical Society

Statins are potent inhibitors of HMG-CoA reductase, the key rate-limiting enzyme

in cholesterol biosynthesis, and are some of the best selling drugs globally. We

have explored the effect of chronic cholesterol depletion induced by mevastatin

on the function of human serotonin1A receptors expressed in CHO cells. An

advantage with statins is that cholesterol depletion is chronic which mimics

physiological conditions. Our results show a significant reduction in the level

of specific ligand binding and G-protein coupling to serotonin1A receptors upon

chronic cholesterol depletion, although the membrane receptor level is not

reduced at all. Interestingly, replenishment of mevastatin-treated cells with

cholesterol resulted in the recovery of specific ligand binding and G-protein

coupling. Treatment of cells expressing serotonin1A receptors with mevastatin

led to a decrease in the diffusion coefficient and an increase in the mobile

fraction of the receptor, as determined by fluorescence recovery after

photobleaching measurements. To the best of our knowledge, these results

constitute the first report describing the effect of chronic cholesterol

depletion on the organization and function of a G-protein-coupled neuronal

receptor. Our results assume significance in view of recent reports highlighting

the symptoms of anxiety and depression in humans upon statin administration, and

the role of serotonin1A receptors in anxiety and depression.