Endocrine Journal 2011, 58 (12), 1021-1028 REVIEW The role of thermosensitive TRP (transient receptor potential) channels in insulin secretion Kunitoshi Uchida1) and Makoto Tominaga1, 2) 1) Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787 Japan 2) Department of Physiological Sciences, The University of Advanced Studies, Aichi 444-8585, Japan Abstract. Insulin secretion from pancreatic β-cells is the only efficient means to decrease blood glucose concentrations. Glucose is the principal stimulator of insulin secretion with the ATP-sensitive K+ channel-voltage-gated Ca2+ channel- mediated pathway being the primary one involved in glucose-stimulated insulin secretion. Recently, several reports demonstrated that some transient receptor potential (TRP) channels are expressed in pancreatic β-cells and contribute to pancreatic β-cell functions. Interestingly, six of them (TRPM2, TRPM4, TRPM5, TRPV1, TRPV2 and TRPV4) are thermosensitive TRP channels. Thermosensitive TRP channels in pancreatic β-cells can function as multimodal receptors and cause Ca2+ influx and membrane depolarization at physiological body temperature. TRPM channels (TRPM2, TRPM4 and TRPM5) control insulin secretion levels by sensing intracellular Ca2+ increase, NAD metabolites, or hormone receptor activation. TRPV2 is involved not only in insulin secretion but also cell proliferation, and is regulated by the autocrine effects of insulin. TRPV1 expressed in sensory neurons is involved in β-cell stress and islet inflammation by controlling neuropeptide release levels. It is thus clear that thermosensitive TRP channels play important roles in pancreatic β-cell functions, and future analyses of TRP channel function will lead to better understanding of the complicated mechanisms involved in insulin secretion and diabetes pathogenesis. Key words: Thermosensitive TRP channel, Insulin secretion, Pancreatic β-cell, Glucose tolerance, Intracellular Ca2+ MOST transient receptor potential (TRP) channels are is now called TRPV1, was isolated from a rodent sen- non-selective cation channels. The name TRP comes sory neuron cDNA library in 1997 and was considered from the prototypical member in Drosophila, where to be a breakthrough for research concerning temper- a mutation resulted in abnormally transient receptor ature sensing [3]. Since then, several TRP channels potential to continuous light [1]. TRP channels are having thermosensitive ability have been identified in now divided into seven subfamilies: TRPC, TRPV, mammals, with nine thermosensitive TRP channels TRPM, TRPML, TRPN, TRPP, TRPA, with six sub- reported in mammals to date (Table 1). These chan- families (all except for TRPN) and 27 channels pres- nels belong to the TRPV, TRPM, and TRPA subfami- ent in humans. TRP channels are expressed in many lies, and their temperature thresholds for activation are tissues and have a wide variety of physiological func- in the range of physiological temperatures, which we tions, including detection of various physical and can discriminate. TRPV1 and TRPV2 are activated chemical stimuli in vision, taste, olfaction, hearing, by elevated temperatures, while TRPM8 and TRPA1 touch, and thermosensation [2]. The gene encoding are activated by cool and cold temperatures. TRPV3, the capsaicin receptor as a noxious heat sensor, which TRPV4, TRPM2, TRPM4 and TRPM5 are activated by warm temperatures. Thermosensitive TRP channels Submitted Jul. 10, 2011; Accepted Jul. 12, 2011 as EJ11-0130 usually function as ‘multimodal receptors’ that respond Released online in J-STAGE as advance publication Jul. 23, 2011 to various chemical and physical stimuli. For example, Correspondence to: Kunitoshi Uchida and Makoto Tominaga, TRPV1, activated by noxious heat (> 42 oC), is also a Division of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Higashiyama receptor for capsaicin, an active ingredient of chili pep- 5-1, Myodaiji, Okazaki, Aichi 444-8787 Japan. pers, and low pH. Activation of these channels could E-mail: [email protected] (KU) and [email protected] (MT) contribute to changes in intracellular Ca2+ concentra- ©The Japan Endocrine Society 1022 Uchida et al. Table 1 Properties of thermosensitive TRP channels and their expression in pancreatic β-cells temperature tissue distribution other stimuli β-cells expression threshold capsaicin, proton, shanshool, allicin, camphor, sensory neuron, resiniferatoxin, vanillotoxin, 2-APB, propofol, TRPV1 > 42°C brain, skin anandamide, arachidonic acid metabolic products RINm5F, INS-1, rat islets (by lipoxygenases), NO, extracellular cation sensory neuron, brain, spinal cord, lung, probenecid, 2-APB, cannabidiol, mechanical TRPV2 > 52°C liver, spleen, colon, stimulation MIN6, mouse β-cells heart, immunocyte skin, sensory neuron, TRPV3 > 32°C brain, spinal cord, camphor, carvacrol, menthol, eugenol, thymol, ─ stomach, colon 2-APB skin, sensory neuron, 4α-PDD, bisandrographolide, citric acid, arachidonic TRPV4 > 27-41°C brain, kidney, lung, acid metabolic products (by epoxygenases), MIN6 inner ear, bladder anandamide, hypoosmolality, mechanical stimulation INS-1, human istets, brain, immunocyte 2+ TRPM2 > 36°C (cyclic) ADPribose, β-NAD, H2O2, intracellular Ca RIN-5F, MIN6, rat etc β-cells,mouse β-cells heart, liver, 2+ INS-1, RINm-5F, Human TRPM4 warm immunocyte etc intracellular Ca β-cells, β-TC3, ENG1G9 TRPM5 warm taste cell intracellular Ca2+ MIN-6, INS-1, mouse β-cells, human pancreas TRPM8 < 27°C sensory neuron menthol, icilin, eucalyptol ─ allyl isothiocyanate, carvacrol, cinnamaldehyde, sensory neuron, allicin, acrolein, icilin, tetrahydrocannabinol, TRPA1 < 17°C inner cell menthol (10-100 μM), formalin, H2O2, alkalization, ─ intracellular Ca2+, NSAIDs, propofol/ isoflurane/ desflurane/ etomidate/ octanol/ hexanol Capsaicin (in capsicum), shanshool (in Zanthoxylum peperitum, Japanese pepper), allicin (in garlic), camphor (in wood of the camphor laurel), resiniferatoxin (in cactus), vanillotoxin (in tarantula toxin), 2-APB (2-aminomethoxydiphenyl borate), probenecid (an anion transporter inhibitor), carvacrol (in oregano), menthol (in mint), eugenol (in savory), thymol (in thyme), 4α-PDD (4α-phorbol 12,13-didecanoate), bisandrographolide (in andrographis), ADP-ribose (adenosine di-phosphoribose), β-NAD (β-nicotinamide dinucleotide), icilin (a super cooling agent), eucalyptol (in eucalyptus), allyl isothiocyanate (in wasabi), cinnamaldehyde (in cinnamon), acrolein (in tear gas), tetrahydrocannabinol (in cannabis plant), NSAIDs (non-steroidal anti- inflammatory drugs), isoflurane/ desflurane/ etomidate/ octanol/ hexanol (all analgesia). 2+ 2+ 2+ tions ([Ca ]i) and control of membrane potentials in for the increase in [Ca ]i is Ca influx through L-type many cell types. VGCCs, but recent electrophysiological studies indi- Insulin secretion from pancreatic β-cells is the only cated that many ion channels can contribute to Ca2+ sig- efficient means to decrease blood glucose concentra- naling and changes in membrane potentials, and their tions. Accordingly, insulin secretion is strictly con- relative importance has been examined [4, 5]. Thus, trolled by glucose, hormones, and autonomic nervous insulin secretion mechanisms are very complicated. system activity. The trigger pathway for glucose-stimu- Several reports showed that TRPC1, TRPC2, TRPC4, lated insulin secretion is generally described as involv- TRPC6, TRPV1, TRPV2, TRPV4, TRPV5, TRPM2, + ing an ATP-sensitive K (KATP) channel-voltage-gated TRPM3, TRPM4, and TRPM5 channels are expressed Ca2+ channel (VGCC)-mediated pathway. In the first in pancreatic β-cells [6-12], and that six (TRPM2, step, glucose is transported into β-cells through glucose TRPM4, TRPM5, TRPV1, TRPV2 and TRPV4) are transporter 2 (GLUT2) to produce a change in the ATP/ thermosensitive TRP channels. Interestingly, among ADP ratio, which in turn generates membrane depolar- the thermosensitive TRP channels expressed in pan- ization through a direct block of KATP channels. VGCCs creas, four channels are warm temperature-sensitive 2+ open upon depolarization, leading to [Ca ]i increase channels (activated around body temperature) (Table 1), 2+ whereupon oscillations of [Ca ]i and membrane poten- indicating that these channels have functions at physi- tials drive pulsatile insulin secretion. The main source ological body temperature conditions that differ from TRP channels and insulin secretion 1023 environmental temperature sensing. In this review, we Glucose and incretin stimulate TRPM2 activation but focus on the involvement of thermosensitive TRP chan- the precise mechanism for modulation of TRPM2 activ- nels (TRPM2, TRPM4, TRPM5, TRPV1, TRPV2 and ity remains unclear. cADPR, reported to be involved TRPV4) in pancreatic β-cell functions, especially in in glucose-stimulated insulin secretion [22], is a candi- insulin secretion, development of type-1 diabetes, and date TRPM2 activator (Fig. 1). Furthermore, the fact the autocrine effects of insulin. that NAD also activates TRPM2 indicates that NAD and its metabolites in concert may activate TRPM2 at TRPM2 body temperature. Protein kinase A (PKA), which is involved in insulin secretion downstream of incretin TRPM2 is a highly Ca2+-permeable cation chan- receptors, potentiates TRPM2 activity [17], suggesting nel that is activated by nicotinamide adenine dinucle- that PKA acts as a modulator of TRPM2 activity,