Ion Channels: Introduction and SOCCs

Ion Channels: Introduction

• Ion channels are protein complexes forming pores allowing ion passage.
• Channels can be "leaky" (always open) or "gated" (ligand-gated or voltage-gated).
• Ion transporters maintain uneven ion distribution across cellular compartments.
• Channels reside in plasma membranes or intracellular organelle membranes.
• Ion flow is driven by concentration and electrical gradients; the cell's negative interior attracts positive ions.
• Chemical synapses use ligand-gated ion channels (LGCs) for intercellular signaling; LGC activation often triggers voltage-gated channels.
• Electrical synapses employ connexin channels for passive ion flow.
• Organelle membrane channels mediate intracellular signaling.

Store-Operated Calcium Channels (SOCCs)

• Cytosolic calcium changes are crucial signals, triggering rapid and slow cellular responses.
• Rapid responses (e.g., neurotransmitter release, muscle contraction) involve voltage-gated calcium channels in excitable cells.
• Slow responses, due to sustained calcium influx via SOCCs, occur in excitable and non-excitable cells; affecting gene transcription, cell differentiation, and migration.
• Response speed depends on channel location and calcium-binding protein distribution.
• Many calcium channels/proteins have EF-hand domains for calcium binding.

Calmodulin (CaM)

• Binds four calcium ions, undergoing a conformational change upon activation.
• Activated CaM regulates: calcineurin (involved in gene transcription via NFAT), CaM-dependent kinases (e.g., in muscle contraction), and calcium pumps/exchangers (removing calcium from the cytosol).
• The change in membrane voltage (Vm), not cytosolic calcium concentration itself, is the primary signal.

Regulating Calcium in/out of the ER

• Ligand-gated ER calcium channels mediate calcium efflux.
• GPCR activation, through PLC and IP3, triggers calcium efflux from the ER (via IP3R).
• RyR channels (RyR-1, RyR-2) on the ER/SR also mediate calcium release; some are physically coupled to L-type calcium channels.

Mitochondria-Associated Membranes (MAMs)

• Close ER-mitochondria contacts.
• VDACs (outer mitochondrial membrane) and MCUs (inner membrane) facilitate calcium influx into mitochondria.
• Grp75 protein links ER channels (like IP3R) to VDACs/MCUs.
• LETM1 and NCLX transport calcium out of mitochondria.

Restoring Low Cytosolic Calcium

• Increased cytosolic calcium activates SERCA (using ATP) to refill ER stores (via Ca2+/CaM).
• Increased cytosolic calcium also activates PMCA (plasma membrane calcium ATPase) and NCLX to transport calcium out of the cell.

Store-Operated Calcium Entry (SOCE): L2

• ER calcium depletion activates STIM1 .
• STIM1 interacts with TRPC1/3 channels, gating them (protein-protein interaction).
• STIM1’s interaction with TRPC channels is dependent on the channel subtype and is dependent on particular charged amino acid residue interactions.
• STIM1 gating of TRPC1/3 channels is dependent on specific charged amino acid interactions between STIM1 and the TRPC1/3 channels.
• SOCC inhibitors include lanthanides (ORAI blockers), 2-APB (transient activator/high-concentration blocker), and BTP2.
• SOCC activators include Gαq-coupled GPCR agonists (increasing PLC/IP3) and compounds depleting ER calcium (ionomycin, thapsigargin).

SOCC Dysregulation and Diseases: L3

Antigen Presentation to T Cells

• APCs (dendritic cells, macrophages) present processed antigens (MHC II) to T helper cells.
• Chemokines attract T cells to APCs.
• CD4+ T cells use TCR (with CD4 assistance) to recognize MHC II/antigen complexes.
• This interaction triggers STIM/ORAI-mediated CRACs, initiating T cell activation, proliferation, and differentiation.

MHC II/Antigen Processing in APCs

• Antigen endocytosis, processing in endosomes/lysosomes, MHC II loading, and presentation on the plasma membrane.

MHC II/TCR Protein Interactions

• CD4 enhances MHC II/TCR binding specificity.
• CD28/CD80 interaction stabilizes the interaction.
• Antigen/TCR binding activates tyrosine kinases (ZAP70, LAT), leading to PLC activation (PLCy1 and PLCb).
• PLC generates IP3 (causing calcium release from ER) and DAG.
• ER calcium depletion activates STIM1/ORAI, mediating calcium influx.
• Increased cytosolic calcium activates calcineurin, which dephosphorylates NFAT, causing its nuclear translocation and gene expression changes (T cell activation).

T Cell Phenotypic Differentiation

• Activated T cells differentiate into Th1, Th2, Th17, and iTreg subsets; each with unique functions, defined by signaling pathways and cytokine environment.

Severe Combined Immunodeficiency (SCID)

• Autosomal recessive disorder caused by ORAI or STIM gene mutations.
• Impairs immune cell function, leading to recurrent infections.
• Affects muscle cells (congenital myopathy) and connective tissue (sweat gland dysfunction).

SOCE Dysregulation in Neurological Diseases: L4

SOCCs in Neurons

• SOCE supports neurogenesis, synaptic formation, plasticity (learning, memory) and underlies slow EPSPs in cerebellar Purkinje neurons (motor learning).

Cerebellum

• Crucial for motor learning.
• Mossy fiber input drives granule neuron activity, influencing Purkinje cell growth and plasticity (motor learning).

Calcium Entry during Slow EPSCs

• Purkinje fiber-Purkinje neuron synapses: NTs trigger ER calcium release and SOCE via STIM1/TRPC3 (mGluR1-dependent).

Diseases

• TRPC3 mutations cause cerebellar ataxia (affecting Purkinje neuron morphology and function as result of altered SOCE.)
• Impaired SOCE may contribute to neurodegenerative diseases (reduced STIM2, impaired SOCE, reduced mature spines in Alzheimer's models).

Explore the fascinating world of ion channels and their critical role in cellular signaling. This quiz delves into the types of channels, their mechanisms, and the significance of store-operated calcium channels in various cellular responses. Test your knowledge on how these proteins influence ion passage and synaptic functions.