TRP Channels Play a Role in Neuronal Ca²⁺ Homeostasis

TRP channels have now been recognized as important players in neurodegenerative diseases and during brain ischemia. In neurons, excessive Ca²⁺ entry occurs via over-activation of glutamate receptors or of a range of channels and transporters (TRPM2, TRPM7, the Na⁺/ Ca²⁺ exchanger NCX, voltage-activated Ca²⁺ channels, and connexin/pannexin hemichannels). Both, TRPM2 and TRPM7 play a potentially toxic role via an increase in [Ca²⁺]_i which in turn triggers a range of downstream neurotoxic cascades, including the uncoupling mitochondrial electron transfer from ATP synthesis, and the activation and overstimulation of enzymes such as calpains and other proteases, protein kinases, nitric oxide synthase (NOS), calcineurin and endonucleases. Blocking of these channels might become an important target for a useful therapeutic strategy for treating ischemic and excitotoxic disorders.Reference Szydlowska and Tymianski³⁰ Alterations in Ca²⁺ homeostasis have been suggested in the onset/progression of neurological diseases, such as Parkinson's, Alzheimer's, bipolar disorder, and Huntington's. On the other hand, TRPC channels form Ca²⁺ entry pathways, which are essential in maintaining cytosolic, ER, and mitochondrial Ca²⁺ levels. Silencing of TRPC1 and TRPC3 has been shown to inhibit neuronal proliferation. Loss of TRPC1 is implicated in neurodegeneration. Thus, dysfunction or loss of function of TRPC channels negatively influences normal physiological processes and play also a role in neurodegeneration due to a defective Ca²⁺ signalling rather than Ca²⁺ overload.Reference Selvaraj, Sun and Singh³¹ However, a massive overactivation of TRPC1 can induce hippocampal glutamate-induced cell death. TRPC1 may represent a promising target for pharmacological interventions to prevent or reduce glutamate-induced neuronal damage.Reference Narayanan, Irmady, Subramaniam, Unsicker and von Bohlen Und Halbach³² Neurotrophins play a significant role in the brain as survival factors, modulators of synaptic transmission and plasticity and they participate in associative learning and memory. As mentioned, BDNF is important for hippocampal synaptic plasticity and neuronal Ca²⁺ homeostasis via TRPC3. This channel mediates changes in neuronal structure including dendritic spine density. Downregulation of TRPC3 prevents an increase in spine density caused by BDNF and is required for spine formation. Dysfunction in the BDNF-TRPC3 interaction may contribute a decrease in spine density that is similar to patterns seen in mental retardation, in particular Rett Syndrome.Reference Amaral, Chapleau and Pozzo-Miller³³ As mentioned already, TRPC3 defects impair motocontrol. TRPC3 were identified as postsynaptic cation channels essential for metabotropic glutamate receptor1-dependent synaptic transmission in cerebellar Purkinje neurons. Motor coordination defects have been described in TRPC3 knockout mice.Reference Hartmann¹⁴ TRPCs play a role in hereditary ataxias, a complex group of neurological disorders characterized by the degeneration of the cerebellum. The dominant mouse model of cerebellar ataxia, moonwalker (Mwk), is caused by a gain-of-function mutation (T635A) in TRPC3. TRPC3 is highly expressed in Purkinje cells during the phase of dendritogenesis. Not unexpectedly (see above), growth and differentiation of Purkinje cell dendritic arbors are dramatically impaired in Mwk mice. TRPC3 therefore plays a crucial role in dendritic development and survival of Purkinje cells mediating cerebellar ataxia. The pathogenesis likely includes altered phosphorylation of TRPC3.Reference Becker³⁴ Considering the similar effects in the trpc3-deficient mouse, obviously opposing aspects of TRPC3 channel activation can lead to the similar phenotype.Reference Trebak³⁵ Spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease, is caused by mutations in a protein kinase PKC. This mutant enzyme fails to phosphorylate TRPC channels, which results in a sustained Ca²⁺ entry and Purkinje cells degeneration in SCA14.Reference Adachi³⁶ TRPC3 is also involved in the development of Parkinson's disease. Parkinsonian movement disorders are often associated with abnormalities in the Substatia nigra (SNr) GABA neuron firing, which is coupled to TRPC3 channels activity, which plays an important role in ensuring the appropriate firing intensity and pattern in SNr GABA projection neurons, which are crucial to movement control.Reference Zhou, Matta and Zhou³⁷

TRP Channels and Epilepsy

Muscarinic stimulation generates prolonged depolarizations called plateau potentials (PP) in hippocampal pyramidal neurons, which are candidates for triggering of the ictal phase of seizures. The underlying mechanism seems to be a gain-of-function of TRPC5 channels due to an increased trafficking to the plasma membrane. Again, this completely novel mechanism, as for so many TRP channels, provides a new understanding of the pathology of epilepsy and defines a new pharmacological target.Reference Tai, Himes and MacVicar³⁸ In addition, the vanilloid TRP channel, TRPV1, seems to be critically involved in the pathogenesis of epilepsy. TRPV1 is now identified as an antiepileptogenic target. Nerve growth factor (NGF) upregulates TRPV1 expression and triggers epileptogenesis. In addition, the endocannabinoid anandamide (AEA) activates TRPV1 endogenously and AEA levels are increased in epilepsy. Activation of TRPV1 also triggers apoptotic neuronal death in chronic epilepsy.Reference Fu, Xie and Zuo³⁹ In general, TRPV1 activation selectively modifies synapses onto interneurons and may affect long-term changes in physiological and pathological circuit behaviour during learning and epileptic activity.Reference Gibson, Edwards, Page, Van Hook and Kauer^40, Reference Alter and Gereau⁴¹

TRPM7 is also involved in the pathogenesis of epilepsy. Lowering extracellular Ca²⁺ and Mg²⁺ activates TRPM7, which results in a the paradoxical Ca²⁺ influx associated with epilepsy.Reference Chen⁴²

Also, a polycystin channel, TRPP2 – better know as PKD2 (mutations lead to polycystic kidney disease) – is involved the pathogenesis of the Joubert syndrome, a rare genetic disorder that affects the cerebellum and includes ataxia, seizures and mental retardation.Reference Cevik⁴³

TRPs, Neurodegenerative Diseases, Defects in Neurodevelopment and Mental Retardation

Because TRP channels are involved in brain development, it is not surprising that more and more evidence is being collected regarding a decisive role of these channels in neurodevelopmental disorders.

The best studied neurodegenerative disease is caused by mutations in the intracellular TRP channel TRPML1 (mucolipidin 1), which causes Mucolipidosis type IV (MLIV). This disease is characterized by severe CNS: developmental, degenerative disorder, motor impairment, mental retardation, optic nerve dystrophy, cornea opaqueness, corpus callosum degeneration, cerebellum degeneration.Reference Bach^44, Reference Bach, Zeevi, Frumkin and Kogot-Levin⁴⁵ TRPML1 fails to function correctly in lysosomal storage diseases (LSDs), which are caused by the inability of cells to process the material captured during endocytosis. While they are essentially diseases of cellular ‘indigestion’, LSDs affect large numbers of cellular activities.Reference Kiselyov, Yamaguchi, Lyons and Muallem⁴⁶ The ‘biogenesis’ model for MLIV pathogenesis suggests that TRP-ML1 modulates postendocytic delivery to lysosomes by regulating interactions between late endosomes and lysosomes. The effects of TRP-ML1 loss on hydrolytic activity have a cumulative effect on lysosome function, resulting in a lag between TRP-ML1 loss and full manifestation of MLIV.Reference Miedel⁴⁷ Disruption of the TRPML1 channel also causes a defective autophagy, which resulted in oxidative stress and impaired synaptic transmission.Reference Venkatachalam^48, Reference Venugopal⁴⁹ TRPML1 has also been described as an iron channel in LEL, which may contribute to the haematological and degenerative symptoms of Mucolipidosis type IV patients.Reference Dong⁵⁰

Two other TRP channels, TRPM2 and TRPM7, are causative, involved in the pathogenesis of the Guamanian amyotrophic lateral sclerosis (ALS-G) and Parkinsonism dementia (PD-G, or Parkinsonism dementia complex, PDC), related neurodegenerative disorders that are found at a relatively high incidence on the Pacific Islands Guam and Rota.Reference Plato⁵¹ These disease result from a complex interaction between genetic predisposition and environmental factors. Two candidate environmental triggers have been identified: (a) altered mineral content of the soil and drinking water and (b) a neurotoxin derived from the cycad plant, a traditional food source in Guam. Channel mutations lead to a significant loss of nigral dopaminergic neurons due to a reduced Mg²⁺ influx in the neuronal cells.Reference Plato⁵² A TRPM7 missense mutation in the C-terminus increases the inhibition of TRPM7 by Mg²⁺ and worsens the Mg²⁺ homeostasis in a Mg²⁺ deficient environment. This defects leads to a reduced intracellular Mg²⁺ concentration described in both ALS-G and PD-G (PDC) patients.Reference Hermosura⁵³ This discovery is especially important because both TRPM7 and TRPM2 have been also implicated in neuronal cell death pathways. TRPM2 senses oxidative stress and TRPM7 is required for cell viability.Reference McNulty and Fonfria⁵⁴ TRPM7 and TRPM2 have been put forward as potential factors in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, strokes and diseases associated with oxidant-mediated neuronal damage.Reference McNulty and Fonfria^54–Reference Li, Westwick, Cox and Poll⁵⁶ Mutations in TRPM2 have been discovered that result in rapidly inactivated channels that are unable to maintain sustained Mg²⁺ influx.Reference Hermosura^57, Reference Hermosura and Garruto⁵⁸ Via other pathomechanisms, TRPM7 is involved in the Familial Alzheimer's Disease (FAD) which is linked to aberrant PI(4,5)P₂ metabolism which in turn causes a dysregulation of this channel. The PI(4,5)P₂ turnover is affected by the presenilin mutants and the cellular PI(4,5)P₂ content correlates with the contents of the 42-residue amyloid β-peptide (A β42). Thus, FAD mutant presenilin generates toxic A β42 levels and causes TRPM7 dysfunction.Reference Landman⁵⁹ TRPM1, the founding member of the TRPM family and until now mainly know as a tumour suppressor and a retinal channel for light perception, could be linked to a complex neurodevelopmental disorder characterized by severe visual impairment, intellectual disability, and refractory epilepsy. This disease is caused by a micro-deletion in chromosome 15q13.3 carrying the trpm1 gene.Reference Lepichon, Bittel, Graf and Yu⁶⁰

TRPs, Schizophrenia and Bipolar Disorders

Several TRP channels have been suggested as players in the pathogenesis of schizophrenia. TRPV1, in cooperation with the endocannabinoid system, influences GABAergic and glutamatergic synapses and play a modulatory function on dopamine transmission. Through these mechanisms TRPV1 and endocannabinoids have an important influence on various neurobiological processes (e.g., control of movement, motivation/reward) and, particularly, on different pathologies affecting these processes such as basal ganglia disorders, schizophrenia, and drug addiction.Reference Fernandez-Ruiz, Hernandez and Ramos⁶¹

Interestingly, some natural compounds that have been used in traditional medicine as anti-depressants have TRP channels as targets. One of these compounds is Incensole acetate, which is released by the burning of resin from the Boswellia plant and has been used for religious and cultural ceremonies for millennia. It activates TRPV3, which is expressed in the brain and causes anxiolytic-like and antidepressive-like behavioral effects.Reference Moussaieff⁶²St. John's Wort has been used medicinally for over 5000 years. Relatively recently, one of its phloroglucinol derivatives, hyperforin, an antidepressive compound, has been identified as an effective activator of TRPC6.Reference Leuner⁶³ Hyperforin has been shown to have cognitive enhancing, memory facilitating properties and has probably neuroprotective effects.Reference Griffith, Varela-Nallar and Dinamarcaand N. Inestrosa⁶⁴ In particular TRPM2, which is highly expressed in the striatum (caudate nucleus and putamen), is supposed to play a key role in bipolar disorders.Reference Aita^65–Reference Xu⁶⁷ Recent case-control studies implicate TRPM2 conferring risk for bipolar disorder (BD) and genetic variants of TRPM2 have been identified to be coupled with BD supporting a role for this channel in the pathogenesis of this disorderReference Xu⁶⁸ (see for a review Ref. Reference Chahl69).

TRPs Channels in Brain Injury and Stroke

Traumatic brain injury elicits a sequence of complex biochemical changes including oxidative stress, oedema, inflammation and excitotoxicity. TRPM2 channels are activated by such conditions, e.g. processes involving oxidative stress. Downregulation of this channel clearly causes a neuroprotective effect in the cerebral cortex and hippocampus after brain injury, oxidative stress, inflammation and neuronal death.Reference Cook, Vink, Helps, Manavis and van den Heuvel⁷⁰

The Ca²⁺ activated TRP channel, TRPM4, is involved in the damaging secondary events that accompany traumatic brain injury (TBI). Changes in capillary permeability result in the extravasation of extracellular fluid, inflammatory cells, and blood, thereby producing cerebral edema, inflammation, and progressive secondary haemorrhage. Inhibition of TRPM4 channels provides beneficial effects in animal models of TBI- and ischemia-associated cerebral edema and secondary haemorrhage.Reference Simard, Kahle and Gerzanich⁷¹ Therefore, TRPM4 inhibition plays a neuroprotective role, reduces brain or spinal chord lesion volume and produces a substantial improvement in neurological function.Reference Gerzanich⁷² Also, TRPM7 is a potential target for neuroprotection after brain injury. Suppressing the expression of TRPM7 in hippocampal CA1 neurons conferred resistance to ischemic cell death, preserved cell function and prevented ischemia-induced deficits in memory.Reference Rempe, Takano and Nedergaard^73, Reference Sun⁷⁴ TBI confers a major burden to Western society and effective treatments are urgently required to improve the long-term deficits of survivors of TBI. Depletion of intracellular Mg²⁺, a symptom of TBI and a reduction of extracellular Ca²⁺ are both associated with poor neurological outcome and are both conditions that activated TRPM7, thereby possibly increasing the Ca²⁺ load of neuronal cells. This leads to secondary injury processes and to cell death following TBI.Reference Cook, Van Den Heuvel and Vink⁷⁵ TRPM7 has been implicated in ischemic brain damage. TRPM7 gene variation might play a role in the risk of ischemic stroke.Reference Romero, Ridker and Zee⁷⁶