TRP channel–associated factors are a novel protein family that regulates TRPM8 trafficking and activity

TRPM8 is a cold sensor that is highly expressed in the prostate as well as in other non-temperature-sensing organs, and is regulated by downstream receptor–activated signaling pathways. However, little is known about the intracellular proteins necessary for channel function. Here, we identify two previously unknown proteins, which we have named “TRP channel–associated factors” (TCAFs), as new TRPM8 partner proteins, and we demonstrate that they are necessary for channel function. TCAF1 and TCAF2 both bind to the TRPM8 channel and promote its trafficking to the cell surface. However, they exert opposing effects on TRPM8 gating properties. Functional interaction of TCAF1/TRPM8 also leads to a reduction in both the speed and directionality of migration of prostate cancer cells, which is consistent with an observed loss of expression of TCAF1 in metastatic human specimens, whereas TCAF2 promotes migration. The identification of TCAFs introduces a novel mechanism for modulation of TRPM8 channel activity.

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TRP channel–associated factors are a novel protein family that regulates TRPM8 trafficking and activity

The Journal of General Physiology ◽

10.1085/jgp.1452oia1 ◽

2015 ◽

Vol 145 (2) ◽

pp. 1452OIA1

Author(s):

Dimitra Gkika ◽

Loic Lemonnier ◽

George Shapovalov ◽

Dmitri Gordienko ◽

Céline Poux ◽

...

Keyword(s):

Associated Factors ◽

Protein Family ◽

Trp Channel ◽

Novel Protein

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Opposing effects of oxidants and antioxidants on K+ channel activity and tone in rat vascular tissue

Experimental Physiology ◽

10.1113/expphysiol.1995.sp003890 ◽

1995 ◽

Vol 80 (5) ◽

pp. 825-834 ◽

Cited By ~ 78

Author(s):

HL Reeve ◽

EK Weir ◽

DP Nelson ◽

DA Peterson ◽

SL Archer

Keyword(s):

Vascular Tissue ◽

K Channel ◽

Channel Activity ◽

Opposing Effects

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Functional Modulation of Cardiac ATP-Sensitive K+ Channels

Physiology ◽

10.1152/physiologyonline.1998.13.3.131 ◽

1998 ◽

Vol 13 (3) ◽

pp. 131-137 ◽

Cited By ~ 1

Author(s):

Masayasu Hiraoka ◽

Tetsushi Furukawa

Keyword(s):

Action Potential ◽

Channel Activity ◽

K Channels ◽

Channel Function ◽

Intracellular Atp ◽

Functional Modulation ◽

Action Potential Shortening

ATP-sensitive K+ (KATP) channels are inhibited by intracellular ATP, but MgATP is necessary to maintain the channel activity. Numerous cofactors modulate channel function. K+ channel openers activate and sulfonylureas inhibit KATP channels. The structure of cardiac KATP channel is a complex of mainly KIR6.2 and SUR2a. Activation of cardiac KATP channels contributes to action potential shortening during ischemia and plays a role in cardioprotection.

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Transient receptor potential (TRP) channel function in the reproductive axis

Cell Calcium ◽

10.1016/j.ceca.2017.04.004 ◽

2017 ◽

Vol 67 ◽

pp. 138-147 ◽

Cited By ~ 5

Author(s):

Viktoria Götz ◽

Sen Qiao ◽

Andreas Beck ◽

Ulrich Boehm

Keyword(s):

Transient Receptor Potential ◽

Receptor Potential ◽

Trp Channel ◽

Channel Function ◽

Reproductive Axis ◽

Transient Receptor

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Molecular Insights into Regulation of L-Type Ca Channel Function

Physiology ◽

10.1152/physiologyonline.1991.6.6.277 ◽

1991 ◽

Vol 6 (6) ◽

pp. 277-281 ◽

Cited By ~ 1

Author(s):

P Lory ◽

G Varadi ◽

A Schwartz

Keyword(s):

Structure Function ◽

Splice Variants ◽

Ca Channel ◽

Gene Products ◽

Ca Channels ◽

Channel Activity ◽

Excitable Cells ◽

Multiple Gene ◽

Channel Function ◽

Voltage Dependent

The diversity of voltage-dependent Ca channels is well documented. How excitable cells produce their specific Ca channel activity is being approached by structure-function studies. The implications of multiple gene products, splice variants, and subunit assembly in Ca channel function are updated in this review.

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Regulation of TRPM8 channel activity by Src‐mediated tyrosine phosphorylation

Journal of Cellular Physiology ◽

10.1002/jcp.29397 ◽

2019 ◽

Vol 235 (6) ◽

pp. 5192-5203 ◽

Cited By ~ 4

Author(s):

Alexandra Manolache ◽

Tudor Selescu ◽

G. Larisa Maier ◽

Mihaela Mentel ◽

Aura Elena Ionescu ◽

...

Keyword(s):

Tyrosine Phosphorylation ◽

Channel Activity ◽

Trpm8 Channel

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Hypertension resistance polymorphisms in ROMK (Kir1.1) alter channel function by different mechanisms

AJP Renal Physiology ◽

10.1152/ajprenal.00257.2010 ◽

2010 ◽

Vol 299 (6) ◽

pp. F1359-F1364 ◽

Cited By ~ 19

Author(s):

Liang Fang ◽

Dimin Li ◽

Paul A. Welling

Keyword(s):

Blood Pressure ◽

Critical Role ◽

Pressure Control ◽

Surface Expression ◽

Protein Product ◽

Sequence Variants ◽

Channel Activity ◽

Loss Of Function ◽

Channel Function ◽

Channel Expression

The renal outer medullary K+ (ROMK) channel plays a critical role in renal sodium handling. Recent genome sequencing efforts in the Framingham Heart Study offspring cohort (Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, and Lifton RP. Nat Genet 40: 592–599, 2008) recently revealed an association between suspected loss-of-function polymorphisms in the ROMK channel and resistance to hypertension, suggesting that ROMK activity may also be a determinant of blood pressure control in the general population. Here we examine whether these sequence variants do, in fact, alter ROMK channel function and explore the mechanisms. As assessed by two-microelectrode voltage clamp in Xenopus oocytes, 3/5 of the variants (R193P, H251Y, and T313FS) displayed an almost complete attenuation of whole cell ROMK channel activity. Surface antibody binding measurements of external epitope-tagged channels and analysis of glycosylation-state maturation revealed that these variants prevent channel expression at the plasmalemma, likely as a consequence of retention in the endoplasmic reticulum. The other variants (P166S, R169H) had no obvious effects on the basal channel activity or surface expression but, instead, conferred a gain in regulated-inhibitory gating. As assessed in giant excised patch-clamp studies, apparent phosphotidylinositol 4,5-bisphosphate (PIP2) binding affinity of the variants was reduced, causing channels to be more susceptible to inhibition upon PIP2 depletion. Unlike the protein product of the major ROMK allele, these two variants are sensitive to the inhibitory affects of a G protein-coupled receptor, which stimulates PIP2 hydrolysis. In summary, we have found that hypertension resistance sequence variants inhibit ROMK channel function by different mechanisms, providing new insights into the role of the channel in the maintenance of blood pressure.

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