Christian Grimm

Christian Grimm
Ludwig-Maximilians-University of Munich | LMU · Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine

Prof. Dr. Dr.

About

121
Publications
17,529
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
4,353
Citations
Additional affiliations
November 2018 - present
Ludwig-Maximilians-University of Munich
Position
  • Professor (Associate)
December 2011 - October 2018
Ludwig-Maximilians-University of Munich
Position
  • Group Leader
September 2009 - June 2011
Pfizer
Position
  • Principal Investigator

Publications

Publications (121)
Article
Lysosomes are cell organelles that degrade macromolecules to recycle their components. If lysosomal degradative function is impaired, e.g., due to mutations in lysosomal enzymes or membrane proteins, lysosomal storage diseases (LSDs) can develop. LSDs manifest often with neurodegenerative symptoms, typically starting in early childhood, and going a...
Article
Full-text available
Two-pore channels are endo-lysosomal cation channels with malleable selectivity filters that drive endocytic ion flux and membrane traffic. Here we show that TPC2 can differentially regulate its cation permeability when co-activated by its endogenous ligands, NAADP and PI(3,5)P2. Whereas NAADP rendered the channel Ca²⁺-permeable and PI(3,5)P2 rende...
Article
Two-pore channels TPC1 and TPC2 are ubiquitously expressed pathophysiologically relevant proteins that reside on endolysosomal vesicles. Here, we review the electrophysiology of these channels. Direct macroscopic recordings of recombinant TPCs expressed in enlarged lysosomes in mammalian cells or vacuoles in plants and yeast demonstrate gating by t...
Article
Full-text available
Despite novel therapy regimens and extensive research, chemoresistance remains a challenge in leukemia treatment. Of note, recent studies revealed lysosomes as regulators of cell death and chemotherapy response, suggesting this organelle is a novel target for chemosensitization. Interestingly, drug-resistant VCR-R CEM acute lymphoblastic leukemia (...
Chapter
Functional characterization of endolysosomal ion channels is challenging due to their intracellular location. With recent advances in endolysosomal patch clamp technology, it has become possible to directly measure ion channel currents across endolysosomal membranes. Members of the transient receptor potential (TRP) cation channel family, namely th...
Article
Full-text available
Liver cancers, including hepatocellular carcinoma (HCC), are the second most lethal cancers worldwide and novel therapeutic strategies are still highly needed. Recently, the endolysosomal cation channel TRPML1 has gained focus in cancer research representing an interesting novel target. We utilized the recently developed isoform-selective TRPML1 ac...
Article
Neurodegenerative diseases (ND) pose a serious health burden to society and healthcare systems alike, with increasing incidence rates especially within ageing populations. Alzheimer's disease (AD) is the most prevalent type of ND or dementia, followed by Parkinson's disease (PD), multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's d...
Article
Full-text available
Endolysosomal cation channels are emerging as key players of endolysosomal function such as endolysosomal trafficking, fusion/fission, lysosomal pH regulation, autophagy, lysosomal exocytosis, and endocytosis. Diseases comprise lysosomal storage disorders (LSDs) and neurodegenerative diseases, metabolic diseases, pigmentation defects, cancer, immun...
Data
Suppl. for Nature Commun., Spix et al., 2022 https://doi.org/10.1038/s41467-021-27860-x Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice
Article
Full-text available
Lung emphysema and chronic bronchitis are the two most common causes of chronic obstructive pulmonary disease. Excess macrophage elastase MMP-12, which is predominantly secreted from alveolar macrophages, is known to mediate the development of lung injury and emphysema. Here, we discovered the endolysosomal cation channel mucolipin 3 (TRPML3) as a...
Chapter
The following chapter summarizes the current knowledge about the slow vacuolar (SV) cation current and two-pore channels (TPCs) in plants and animals. TPCs are ubiquitously expressed in plant vacuoles and the animal endolysosomal system. Evolutionary aspects of TPCs in the plant and animal kingdoms will be discussed. Differences in plant and animal...
Preprint
Full-text available
In response to pro-inflammatory challenges including pathogenic attack and tissue damage, the endothelial cell surface is rearranged to present leukocyte-engaging cell surface receptors. The initial contact needed for leukocyte tethering and rolling is mediated via adhesion demand-driven exocytosis of Weibel-Palade bodies (WPB) that contain the leu...
Article
Full-text available
Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent-conjugated bacterial toxins to label Gb3 to develop a cell-based hig...
Article
Full-text available
Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly and can be classified either as dry or as neovascular (or wet). Neovascular AMD is characterized by a strong immune response and the inadequate release of cytokines triggering angiogenesis and induction of photoreceptor death. The pathomechanisms of AMD a...
Article
Full-text available
Microphthalmia-associated transcription factor (MITF) is the principal transcription factor regulating pivotal processes in melanoma cell development, growth, survival, proliferation, differentiation and invasion. In recent years, convincing evidence has been provided attesting key roles of endolysosomal cation channels, specifically TPCs and TRPML...
Article
NAADP (nicotinic acid adenine dinucleotide phosphate) is a potent second messenger releasing Ca²⁺ from endolysosomes through two-pore channels (TPCs) and from the endoplasmic reticulum (ER) through type 1 ryanodine receptors (RyR1). How NAADP activates these channels, whether directly or indirectly, has been a matter of debate for more than a decad...
Article
Full-text available
Two-pore channel 2 (TPC2) resides in endolysosomal membranes but also in lysosome-related organelles such as the melanin producing melanosomes. Gain-of-function polymorphisms in hTPC2 are associated with decreased melanin production and blond hair color. Vice versa genetic ablation of TPC2 increases melanin production. We show here an inverse corre...
Article
Full-text available
The cation channel TRPML1 is an important regulator of lysosomal function and autophagy. Loss of TRPML1 is associated with neurodegeneration and lysosomal storage disease, while temporary inhibition of this ion channel has been proposed to be beneficial in cancer therapy. Currently available TRPML1 channel inhibitors are not TRPML isoform selective...
Article
Full-text available
Lysosomes are acidic Ca ²⁺ stores often mobilised in conjunction with endoplasmic reticulum (ER) Ca ²⁺ stores. GPN is a widely used lysosomotropic agent that evokes cytosolic Ca ²⁺ signals in many cells. But whether these signals are due to a primary action on lysosomes is unclear in light of recent evidence showing GPN mediates direct ER Ca ²⁺ rel...
Article
Two pore channels (TPCs) and mucolipins (TRPML) are the most prominent cation channels expressed in endolysosomes. Recently, roles of TPCs and TRPML2 have been revealed in regulating and detecting osmotically-driven changes in the surface-to-volume ratio of endolysosomes to promote endocytic and recycling traffic. TPCs and TRPML2 are highly express...
Article
The role of two-pore channel 2 (TPC2), one of the few cation channels localized on endolysosomal membranes, in cancer remains poorly understood. Here, we report that TPC2 knockout reduces proliferation of cancer cells in vitro, affects their energy metabolism, and successfully abrogates tumor growth in vivo. Concurrently, we have developed simplifi...
Article
Full-text available
The endo-lysosomal two-pore channel (TPC2) has been established as an intracellular cation channel of significant physiological and pathophysiological relevance in recent years. For example, TPC2 -/- mice show defects in cholesterol degradation, leading to hypercholesterinemia; TPC2 absence also results in mature-onset obesity, and a role in glucag...
Article
Full-text available
Endolysosomes are dynamic, intracellular compartments, regulating their surface-to-volume ratios to counteract membrane swelling or shrinkage caused by osmotic challenges upon tubulation and vesiculation events. While osmosensitivity has been extensively described on the plasma membrane, the mechanisms underlying endolysosomal surface-to-volume rat...
Article
The old Greek saying “Panta Rhei” (“everything flows”) is true for all life and all living things in general. It also becomes nicely evident when looking closely into cells. There, material from the extracellular space is taken up by endocytic processes and transported to endosomes where it is sorted either for recycling or degradation. Cargo is al...
Article
The members of the TRPML subfamily of non-selective cation channels (TRPML1-3) are involved in the regulation of important lysosomal and endosomal functions, and mutations in TRPML1 are associated with the neurodegenerative lysosomal storage disorder mucolipidosis type IV. For in-depth investigation of functions and (patho)physiological roles of TR...
Article
Full-text available
Ischemia-reperfusion-induced edema (IRE) one of the most significant causes of mortality after lung transplantation can be mimicked ex-vivo in isolated perfused mouse lungs (IPL). Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel studied in endothelium, while its role in the lung epithelium remains elusive. Here we...
Chapter
Among the infectious diseases caused by pathogenic microorganisms such as bacteria, viruses, parasites, or fungi, the most prevalent ones today are malaria, tuberculosis, influenza, HIV/AIDS, Ebola, dengue fever, and methicillin-resistant Staphylococcus aureus (MRSA) infection, and most recently Covid-19 (SARS-CoV2). Others with a rather devastatin...
Article
Full-text available
Mast cells and basophils are main drivers of allergic reactions and anaphylaxis, for which prevalence is rapidly increasing. Activation of these cells leads to a tightly controlled release of inflammatory mediators stored in secretory granules. The release of these granules is dependent on intracellular calcium (Ca ²⁺ ) signals. Ca ²⁺ release from...
Article
Full-text available
Transient receptor potential (TRP) or transient receptor potential channels are a highly diverse family of mostly non-selective cation channels. In the mammalian genome, 28 members can be identified, most of them being expressed predominantly in the plasma membrane with the exception of the mucolipins or TRPMLs which are expressed in the endo-lysos...
Article
Full-text available
Two pore channels (TPCs) have been a hot topic in recent literature. Their involvement in various diseases like viral infections and cancer is of great interest for drug research. Due to their localization in the endo‐lysosomal system and the lack of cell permeable activators, complex techniques were required for studying channel functions. Here we...
Poster
Abnormal release of Ca2+ from intracellular stores in cardiomyocytes is a cause of ventricular arrhythmias associated with cardiac remodeling. Recently, it was shown: First, that nicotinic acid adenine dinucleotide phosphate (NAADP) in cardiomyocytes activates Two-pore channels (TPC) after catecholamine stimulation and second, that TPC2 at lysosoma...
Article
The ongoing SARS-CoV2 outbreak has developed into a global pandemic. Despite previous outbreaks of SARS-CoV and the related MERS-CoV in recent years, neither a vaccine nor any other medication for an effective treatment are currently available. Endo-lysosomal two-pore cation channels have now emerged as potential novel targets for SARS-CoV treatmen...
Article
Full-text available
Cytotoxic lymphocytes, including natural killer (NK) cells and T cells are distinguished by their ability to eliminate target cells through release of secretory lysosomes. Conventional lysosomes and secretory lysosomes are part of the pleomorphic endolysosomal system and characterized by its highly dynamic nature. Several calcium-permeable TRP calc...
Article
Full-text available
Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high throughput screen identified...
Article
Full-text available
Background: In 1883, Ilya Mechnikov discovered phagocytes and established the concept of phagocytosis by macrophages. In 1908, he was awarded the Nobel Prize in Physiology/Medicine for his findings, which laid the foundations for today's understanding of the innate immune response. Only in the 1960s, Max Cooper and Robert Good significantly advance...
Article
Full-text available
The lysosomal calcium channel TRPML1, whose mutations cause the lysosomal storage disorder (LSD) mucolipidosis type IV (MLIV), contributes to upregulate autophagic genes by inducing the nuclear translocation of the transcription factor EB (TFEB). Here we show that TRPML1 activation also induces autophagic vesicle (AV) biogenesis through the generat...
Article
Introduction Two-pore channel 2 (TPC2) represents an exceptional ion channel due to its localization on lysosomes1. TPC2 is overexpressed in several cancer types, e.g. in prostate cancer, and its expression is associated with poor survival probability2. To date, a role of TPC2 in leukemia has not been investigated. Pharmacologic inhibition of TPC2...
Preprint
Full-text available
Ischemia-reperfusion(IR)-induced edema formation can be mimicked ex-vivo in isolated perfused mouse lungs (IPL). Here we show enhanced edema formation in transient receptor potential vanilloid 4 (TRPV4)-deficient (TRPV4-/-) IPL compared to wild-type (WT) controls in response to IR, indicating a protective role of TRPV4 to maintain the alveolar epit...
Article
Full-text available
Inhibitory signaling during natural killer (NK) cell education translates into increased responsiveness to activation; however, the intracellular mechanism for functional tuning by inhibitory receptors remains unclear. Secretory lysosomes are part of the acidic lysosomal compartment that mediates intracellular signalling in several cell types. Here...
Article
Full-text available
Inhibitory signaling during natural killer (NK) cell education translates into increased responsiveness to activation; however, the intracellular mechanism for functional tuning by inhibitory receptors remains unclear. Secretory lysosomes are part of the acidic lysosomal compartment that mediates intracellular signalling in several cell types. Here...
Article
Full-text available
Intestinal handling of dietary proteins usually prevents local inflammatory and immune responses and promotes oral tolerance. However, in ~ 1% of the world population, gluten proteins from wheat and related cereals trigger an HLA DQ2/8-restricted TH1 immune and antibody response leading to celiac disease. Prior epithelial stress and innate immune a...
Article
Introduction Chemoresistance represents a major problem for the treatment of leukemia patients, which frequently manifests in the multidrug resistance (MDR) phenotype1. The drug refractoriness to structurally related and unrelated drugs can be caused by the P-glycoprotein (P-gp), an efflux pump belonging to the superfamily of ATP-binding cassette (...
Article
Full-text available
Cytokines and chemokines are produced and secreted by a broad range of immune cells including macrophages. Remarkably, little is known about how these inflammatory mediators are released from the various immune cells. Here, the endolysosomal cation channel TRPML2 is shown to play a direct role in chemokine trafficking and secretion from murine macr...
Article
Full-text available
Background: The endolysosomal, non-selective cation channels, two-pore channels (TPCs) and mucolipins (TRPMLs), regulate intracellular membrane dynamics and autophagy. While partially compensatory for each other, isoform-specific intracellular distribution, cell-type expression patterns, and regulatory mechanisms suggest different channel isoforms...
Preprint
Full-text available
Inhibitory signaling during natural killer (NK) cell education translates into increased responsiveness to activation; however the intracellular mechanism for functional tuning by inhibitory receptors remains unclear. We found that educated NK cells expressing self-MHC specific inhibitory killer cell immunoglobulin-like receptors (KIR) show accumul...
Preprint
Our work on the cumulative NK cell functional phenotype that develops under inhibitory receptors, on biorXiv https://www.biorxiv.org/content/early/2018/04/24/305862
Article
Full-text available
The endolysosomal system (ES) consists of lysosomes; early, late, and recycling endosomes; and autophagosomes. It is a key regulator not only of macromolecule degradation and recycling, plasma membrane repair, homeostasis, and lipid storage, but also of antigen presentation, immune defense, cell motility, cell death signaling, tumor growth, and can...
Article
Full-text available
Recombinant TWIK2 channels produce weak basal background K+ currents. Current amplitudes depend on the animal species the channels have been isolated from and on the heterologous system used for their re-expression. Here we show that this variability is due to a unique cellular trafficking. We identified three different sequence signals responsible...
Article
Full-text available
Two-pore channels (TPCs) are localized in endo-lysosomal compartments and assumed to play an important role for vesicular fusion and endosomal trafficking. Recently, it has been shown that both TPC1 and 2 were required for host cell entry and pathogenicity of Ebola viruses. Here, we investigate the cellular function of TPC1 using protein toxins as...
Article
Two-pore channels (TPCs) are endolysosomal cation channels. Two members exist in humans, TPC1 and TPC2. Functional roles associated with the ubiquitously expressed TPCs include VEGF-induced neoangiogenesis, LDL-cholesterol trafficking and degradation, physical endurance under fasting conditions, autophagy regulation, the acrosome reaction in sperm,...
Article
According to proteomics analyses, more than 70 different ion channels and transporters are harbored in membranes of intracellular compartments such as endosomes and lysosomes. Malfunctioning of these channels has been implicated in human diseases such as lysosomal storage disorders, neurodegenerative diseases and metabolic pathologies, as well as i...