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TRPC5

Official Full Name
transient receptor potential cation channel subfamily C member 5
Organism
Homo sapiens
GeneID
7224
Background
This gene belongs to the transient receptor family. It encodes one of the seven mammalian TRPC (transient receptor potential channel) proteins. The encoded protein is a multi-pass membrane protein and is thought to form a receptor-activated non-selective calcium permeant cation channel. The protein is active alone or as a heteromultimeric assembly with TRPC1, TRPC3, and TRPC4. It also interacts with multiple proteins including calmodulin, CABP1, enkurin, Na(+)-H+ exchange regulatory factor (NHERF ), interferon-induced GTP-binding protein (MX1), ring finger protein 24 (RNF24), and SEC14 domain and spectrin repeat-containing protein 1 (SESTD1). [provided by RefSeq, May 2010]
Synonyms
TRP5; PPP1R159;
Bio Chemical Class
Transient receptor potential catioin channel
Protein Sequence
MAQLYYKKVNYSPYRDRIPLQIVRAETELSAEEKAFLNAVEKGDYATVKQALQEAEIYYNVNINCMDPLGRSALLIAIENENLEIMELLLNHSVYVGDALLYAIRKEVVGAVELLLSYRRPSGEKQVPTLMMDTQFSEFTPDITPIMLAAHTNNYEIIKLLVQKRVTIPRPHQIRCNCVECVSSSEVDSLRHSRSRLNIYKALASPSLIALSSEDPILTAFRLGWELKELSKVENEFKAEYEELSQQCKLFAKDLLDQARSSRELEIILNHRDDHSEELDPQKYHDLAKLKVAIKYHQKEFVAQPNCQQLLATLWYDGFPGWRRKHWVVKLLTCMTIGFLFPMLSIAYLISPRSNLGLFIKKPFIKFICHTASYLTFLFMLLLASQHIVRTDLHVQGPPPTVVEWMILPWVLGFIWGEIKEMWDGGFTEYIHDWWNLMDFAMNSLYLATISLKIVAYVKYNGSRPREEWEMWHPTLIAEALFAISNILSSLRLISLFTANSHLGPLQISLGRMLLDILKFLFIYCLVLLAFANGLNQLYFYYETRAIDEPNNCKGIRCEKQNNAFSTLFETLQSLFWSVFGLLNLYVTNVKARHEFTEFVGATMFGTYNVISLVVLLNMLIAMMNNSYQLIADHADIEWKFARTKLWMSYFDEGGTLPPPFNIIPSPKSFLYLGNWFNNTFCPKRDPDGRRRRRNLRSFTERNADSLIQNQHYQEVIRNLVKRYVAAMIRNSKTHEGLTEENFKELKQDISSFRYEVLDLLGNRKHPRSFSTSSTELSQRDDNNDGSGGARAKSKSVSFNLGCKKKTCHGPPLIRTMPRSSGAQGKSKAESSSKRSFMGPSLKKLGLLFSKFNGHMSEPSSEPMYTISDGIVQQHCMWQDIRYSQMEKGKAEACSQSEINLSEVELGEVQGAAQSSECPLACSSSLHCASSICSSNSKLLDSSEDVFETWGEACDLLMHKWGDGQEEQVTTRL
Open
Disease
Chronic kidney disease, Depression
Approved Drug
0
Clinical Trial Drug
2 +
Discontinued Drug
0

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Detailed Information

The TRPC5 (Transient Receptor Potential Cation Channel Subfamily C Member 5) gene is located on the X chromosome at the q23 region and encodes a protein belonging to the C subfamily of the TRP (transient receptor potential) channel family. TRPC5 is a multi-pass transmembrane, non-selective cation channel primarily permeable to calcium (Ca²⁺) and sodium (Na⁺). On the cell membrane, it can form homotetramers or heteromeric complexes with TRPC1, TRPC3, and TRPC4.

Structurally, TRPC5 contains six transmembrane segments (S1–S6), with the pore region located between S5 and S6. Its cytoplasmic domains include multiple functional motifs, such as N-terminal ankyrin repeats and a C-terminal TRP domain, which enable interactions with a variety of regulatory proteins. TRPC5 has been shown to interact with calmodulin, CABP1, enkurin, NHERF, MX1, RNF24, and SESTD1, among others, which collectively regulate its channel activity and subcellular localization.

The channel exhibits multimodal activation mechanisms. It can be indirectly regulated by phosphoinositide signaling downstream of GPCRs and receptor tyrosine kinases or directly activated by intracellular calcium store depletion. TRPC5 also responds to changes in membrane potential, osmotic pressure, and extracellular pH, functioning as a key integrator of environmental and endogenous signals. In the brain, TRPC5 is primarily expressed in POMC neurons of the arcuate nucleus and oxytocin neurons of the paraventricular nucleus, playing roles in energy balance and emotional behavior regulation. Its expression displays sexual dimorphism, which may contribute to its involvement in sex-specific disorders.

Figure 1. A cellular model of insulin and leptin signalling in pro-opiomelanocortinFigure 1. A cellular model of insulin and leptin signalling in pro-opiomelanocortin (POMC) neurones. (Qiu J, et al., 2018)

Evolutionarily, TRPC5 is highly conserved among mammals, with significant sequence and functional homology between humans and mice. This conservation provides a solid foundation for using genetically engineered mouse models to study human disease mechanisms. TRPC5 has been shown to regulate evolutionarily conserved innate behaviors, including feeding, fear responses, social interactions, and maternal behavior, which are essential for survival and reproduction.

Central Regulation of Energy Metabolism

TRPC5 is highly expressed in POMC neurons of the hypothalamic arcuate nucleus, which serve as critical regulators of central energy balance. Metabolic hormones such as leptin and serotonin activate TRPC5 channels on these neurons, inducing depolarization and enhancing firing activity to transmit anorexigenic signals and promote energy expenditure. Dysfunction of TRPC5 disrupts this signaling, impairing appetite suppression and leading to hyperphagia and weight gain. Experimental mouse models with TRPC5 loss-of-function mutations replicate these phenotypes, demonstrating reduced sensitivity of POMC neurons to metabolic hormones and impaired central-peripheral metabolic coordination.

Beyond central effects, TRPC5 deficiency can directly impact peripheral tissues such as adipocytes, contributing to a combined mechanism of energy imbalance involving both central and peripheral systems.

Role in Emotional Behavior and Social Function

TRPC5 also plays a crucial role in emotional and social behaviors. In oxytocin neurons of the paraventricular nucleus, TRPC5 regulates calcium influx, influencing oxytocin synthesis and release. Oxytocin, often referred to as the "social bonding hormone," is critical for emotional attachment, stress responses, and maternal behavior. Loss of TRPC5 function has been associated with anxiety-like behaviors, social withdrawal, and impaired adaptation to sensory stimuli. Animal studies indicate that TRPC5 deficiency in females can impair maternal care, reduce nest-building ability, and decrease responsiveness to offspring, reflecting core features of depressive-like behaviors. Mechanistic studies link these behavioral deficits to reduced excitability of oxytocin neurons and insufficient oxytocin release. Restoration of TRPC5 specifically in oxytocin neurons can rescue these phenotypes, supporting a causal role for TRPC5 in modulating maternal behavior and emotional regulation.

Molecular Pathophysiology

TRPC5 functions through two partially independent yet interconnected neural pathways: the POMC neuron pathway mediates energy balance, while the oxytocin neuron pathway governs emotional behavior and maternal care. This dual pathway mechanism explains how TRPC5 deficiency can lead to coexisting metabolic and affective disturbances within the same individual. The understanding of these pathways provides molecular markers for disease diagnosis and offers a theoretical basis for targeted therapeutic interventions.

Intervention Strategies

Potential therapeutic strategies targeting TRPC5 include hormone replacement approaches, small-molecule channel modulators, and gene therapy. Exogenous oxytocin administration in animal models can restore energy balance, improve maternal behaviors, and alleviate anxiety-like symptoms. TRPC5-specific agonists, such as benzothiadiazine derivatives, selectively enhance channel activity and have demonstrated efficacy in reducing food intake and improving emotional behaviors in animal studies, though their effects are dependent on the presence of functional TRPC5.

Gene therapy approaches offer additional promise. Viral-mediated re-expression of TRPC5 in targeted neuronal populations can reverse metabolic and behavioral deficits in animal models, providing a potential strategy for treating severe genetic deficiencies, though clinical translation requires overcoming delivery and immunogenicity challenges.

Diagnostic and Precision Medicine Applications

TRPC5 has emerged as a candidate for genetic screening in disorders involving early-onset obesity, anxiety, and postpartum depression. Its location on the X chromosome contributes to sex-specific phenotypic expression: males with hemizygous deletions exhibit complete phenotypes, while females with heterozygous variants show variable expressivity due to X-chromosome inactivation. Recognizing this sexual dimorphism is important for developing gender-specific preventive and therapeutic strategies.

Reference

  1. Du SL, Jia ZQ, Zhong JC, et al. TRPC5 in cardiovascular diseases. Rev Cardiovasc Med. 2021 Mar 30;22(1):127-135.

  2. Khare P, Chand J, Ptakova A, et al. The TRPC5 receptor as a pharmacological target for pain and metabolic disease. Pharmacol Ther. 2024 Nov;263:108727.

  3. Sharma S, Hopkins CR. Review of Transient Receptor Potential Canonical (TRPC5) Channel Modulators and Diseases. J Med Chem. 2019 Sep 12;62(17):7589-7602.

  4. Plant TD, Schaefer M. TRPC4 and TRPC5: receptor-operated Ca2+-permeable nonselective cation channels. Cell Calcium. 2003 May-Jun;33(5-6):441-50.

  5. Qiu J, Wagner EJ, Rønnekleiv OK, et al. Insulin and leptin excite anorexigenic pro-opiomelanocortin neurones via activation of TRPC5 channels. J Neuroendocrinol. 2018 Feb;30(2):10.

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