| AMPA Receptor | iGluR1–4 (Ionotropic) | Na⁺ in, K⁺ out | Postsynaptic membrane (dendritic spines in CNS neurons) | Ligand-gated (fast excitatory) | Primary fast excitatory response to glutamate; drives rapid depolarization and helps prime NMDA receptors. | CNQX, NBQX | ↓ Fast excitatory transmission → sedation, reduced neural excitability |
| NMDA Receptor | iGluR with Mg²⁺ block | Na⁺, Ca²⁺ in; K⁺ out | Postsynaptic membrane (CNS neurons, often colocalized with AMPA) | Ligand-gated (requires depolarization to remove Mg²⁺ block) | Needs glutamate + co-agonist (glycine/D-serine) + depolarization; allows Ca²⁺ influx → activates CaMKII, CREB, nitric oxide synthase, etc.; crucial in synaptic plasticity (LTP/LTD). | APV/AP5, MK-801, Ketamine, PCP, Memantine | ↓ Ca²⁺ influx → decreased excitatory transmission, potential analgesia, sedation, dissociation, or hallucinations (depending on the context) |
| Kainate Receptor | iGluR5–7, KA1–2 | Na⁺ in, K⁺ out | Pre- and postsynaptic membranes in certain CNS neurons | Ligand-gated (fast excitatory) | Another ionotropic glutamate receptor; typically less Ca²⁺ permeable than NMDA; modulates presynaptic release and postsynaptic excitability. | CNQX | ↓ Excitatory transmission (somewhat less common target than AMPA/NMDA) |
| TRPV Channels | Transient Receptor Potential | Generally non-selective cation (Ca²⁺, Na⁺) | Plasma membrane of sensory neurons, epithelial cells, etc. | Ligand / voltage / temperature-gated | Respond to temp, chemicals (e.g., capsaicin, menthol), osmotic stress; important in pain, taste, thermoregulation. | Capsazepine (TRPV1), various specific antagonists | ↓ Sensory/pain signals, altered thermoregulation |
| L-type VGCC | Caᵥ1.x (DHP-sensitive) | Ca²⁺ in | Plasma membrane of muscle cells (skeletal, cardiac, smooth), neurons, endocrine cells | Voltage-gated Ca²⁺ channel | Key for excitation–contraction coupling in muscle (including heart), endocrine secretion, neuronal firing; blocked by dihydropyridines (antihypertensives). | Nifedipine, Verapamil, Diltiazem (DHPs, non-DHPs) | ↓ Ca²⁺ influx → relaxation of smooth/cardiac muscle (↓ BP), can affect conduction in SA/AV node |
| Ryanodine Receptor (RyR) | - | Ca²⁺ release from SR / ER | Sarcoplasmic/Endoplasmic Reticulum Membrane in muscle & neurons | Intracellular ligand-gated (Ca²⁺ or caffeine) | Releases Ca²⁺ from SR/ER, driving muscle contraction or neuronal Ca²⁺ signals. | High [Ryanodine], Dantrolene | Dantrolene ↓ muscle contraction (used in malignant hyperthermia); excessive Ryanodine can lock RyR in open/closed states |
| ORAI1 + STIM1 (CRAC Channel) | Store-Operated Ca²⁺ Entry | Ca²⁺ in | STIM1 in ER membrane, ORAI1 in plasma membrane | STIM senses ER Ca²⁺ depletion → ORAI1 opens | Maintains or refills intracellular Ca²⁺ stores when ER Ca²⁺ is low; vital in T-cell activation and many other cell signaling pathways. | GSK-7975A, BTP2 (experimental) | ↓ Immune cell activation, reduced store-operated Ca²⁺ entry |
| NCX | Na⁺/Ca²⁺ Exchanger | 3 Na⁺ in ↔ 1 Ca²⁺ out | Plasma membrane (e.g., cardiac myocytes, neurons); can also be on some organelle membranes | Electrogenic antiporter | Lowers cytosolic Ca²⁺ by using Na⁺ gradient (set by Na⁺/K⁺-ATPase). Can reverse if Na⁺ gradient is reversed; important in cardiac myocytes. | KB-R7943, SN-6 | If blocked, can ↑ cytosolic Ca²⁺ (potentially arrhythmogenic in heart) |
| PMCA | Plasma Membrane Ca²⁺-ATPase | Ca²⁺ out + H⁺ in | Plasma membrane (ubiquitous in eukaryotic cells) | Primary ATPase | Fine-tunes resting Ca²⁺ by actively pumping Ca²⁺ out of the cell; high affinity, low capacity. | Rarely targeted clinically | If inhibited, cytosolic Ca²⁺ remains elevated → potential excitotoxicity |
| SERCA | Sarco/Endoplasmic Reticulum | Ca²⁺ into ER / SR | SR/ER membrane of muscle cells & most other cells | Primary ATPase | Pumps cytosolic Ca²⁺ back into ER/SR; crucial for muscle relaxation, maintaining Ca²⁺ stores for release upon next stimulus. | Thapsigargin | ↑ Cytosolic Ca²⁺ → depletion of ER stores, triggers ER stress, can lead to apoptosis |
| VDAC | Voltage-Dependent Anion Channel | Small anions (ATP, ADP) & can pass Ca²⁺ | Outer mitochondrial membrane | Mitochondrial outer membrane pore | Regulates metabolite exchange; Ca²⁺ entry into mitochondria via VDAC can help buffer cytosolic Ca²⁺ or trigger apoptosis if overloaded. | No common widely used “blockers” in clinic | Inhibiting VDAC → disrupts ATP transport, possibly block Ca²⁺ uptake into mitochondria |
| Na⁺/K⁺-ATPase | Sodium-Potassium Pump | 3 Na⁺ out, 2 K⁺ in | Plasma membrane (basolateral in many epithelial cells) | Primary ATPase | Maintains electrochemical gradients essential for RMP and secondary transport (NCX, SGLT, etc.). | Ouabain, Digoxin | ↑ Intracellular Na⁺ → can indirectly ↑ intracellular Ca²⁺ (via NCX reversal), used to ↑ cardiac contractility in heart failure |
| NHE (Na⁺/H⁺ Exchanger)** | - | Na⁺ in ↔ H⁺ out | Plasma membrane (widespread in many tissues) | Electroneutral antiporter | Regulates intracellular pH by extruding H⁺; helps control cell volume. | Amiloride (also blocks ENaC) | ↑ Intracellular H⁺ (lower pH), can lead to changes in pH homeostasis |
| HCO₃⁻ Transporters | AE (Cl⁻/HCO₃⁻ exchangers), NBC | Cl⁻/HCO₃⁻, or Na⁺/HCO₃⁻ co-transport | Plasma membrane of RBCs, kidney tubule cells, other tissues | Exchanger / Co-transporter | Maintain acid-base balance, RBC gas transport (e.g., band 3 in RBCs), pH regulation in various tissues. | DIDS (4,4’-Diisothiocyano-2,2’-stilbenedisulfonate) | ↓ Bicarbonate transport → altered pH regulation, RBC gas exchange |
| Proton Pump (V-ATPase) | Vacuolar H⁺-ATPase | H⁺ into vesicles (lysosomes, endosomes) | Endosome, Lysosome, Golgi membranes (also some plasma membranes) | Primary ATPase (vacuolar type) | Acidifies intracellular organelles; crucial for protein degradation (lysosomes), receptor recycling (endosomes), and more. | Bafilomycin A1, Concanamycin A | ↑ Vesicular pH (less acidic) → disrupts lysosomal function, endocytic pathway, autophagy |
| Lysosome / Endosome Ca²⁺ | TPC (Two-Pore Channels) | Ca²⁺ from endosomes/lysosomes | Endosomal/Lysosomal membranes | Ligand-gated (NAADP, etc.) | Releases Ca²⁺ from acidic organelles to modulate local or global Ca²⁺ signals; involved in many cell signaling cascades. | No major clinical drugs widely used | ↓ Endolysosomal Ca²⁺ release → can affect autophagy, trafficking, and local Ca²⁺ dynamics |
| PIP₂ | Phosphatidylinositol 4,5-bisphosphate | Membrane lipid (precursor for IP₃, DAG) | Inner leaflet of the plasma membrane | Second messenger reservoir | Hydrolyzed by PLC → IP₃ (releases Ca²⁺ from ER) + DAG (activates PKC). | U73122 (PLC inhibitor) | ↓ IP₃ & DAG → attenuated Ca²⁺ release from ER and PKC-dependent pathways |
| EAAT | Excitatory Amino Acid Transporter | Glutamate reuptake | Plasma membrane of neurons and glial cells | High-affinity co-transport (Na⁺-dependent) | Clears glutamate from synapse, preventing excitotoxicity. | TBOA (DL-threo-β-benzyloxyaspartate) | ↑ Extracellular glutamate → risk of excitotoxicity |
| GABAAR | Ionotropic GABA receptor | Cl⁻ in | Postsynaptic membrane in CNS inhibitory synapses | Ligand-gated (inhibitory) | Causes hyperpolarization (fast IPSPs). Target of benzodiazepines (↑ frequency of channel opening). | Bicuculline (competitive), Picrotoxin (channel block) | ↓ GABAA function → excitatory shift, potential seizures |
| GABABR | Metabotropic GABA receptor | - | Both pre- and postsynaptic in CNS (slower inhibitory synapses) | GPCR (Gi/o) | Slower inhibitory effects (↓ adenylyl cyclase, ↑ K⁺ efflux or ↓ Ca²⁺ influx). | Phaclofen, Saclofen | ↓ Slow inhibitory signaling → potential seizures, spasticity |
| Glycine Receptor | Ionotropic Gly receptor | Cl⁻ in | Postsynaptic membrane in spinal cord, brainstem | Ligand-gated (inhibitory) | Major inhibitory receptor in spinal cord, brainstem. | Strychnine | ↓ Inhibition → muscle spasms, convulsions |
| Nicotinic AChR | Ionotropic (e.g., NM type) | Na⁺, K⁺ (some subtypes pass Ca²⁺) | Neuromuscular junction (Nm), Autonomic ganglia (Nn), some CNS | Ligand-gated (fast excitatory) | Found at NMJ + autonomic ganglia; binds ACh → depolarization, muscle contraction in skeletal muscle, or excitatory transmission in ganglia. | Curare (tubocurarine), α-bungarotoxin | ↓ Neuromuscular transmission → paralysis |
| Muscarinic AChR | GPCR (M1–M5) | - | Parasympathetic target organs, CNS, some presynaptic membranes | Metabotropic (Gq, Gi, Gs) | Parasympathetic effects (↓ HR, ↑ secretions, etc.), CNS roles; M1, M3, M5 typically Gq; M2, M4 typically Gi. | Atropine (non-selective), Scopolamine | ↓ Parasympathetic tone → tachycardia, dry mouth, urinary retention, etc. |
| NH₃/NH₄⁺ Buffer System | Ammonia buffer, NH₃ ↔ NH₄⁺ | H⁺ binding to NH₃ to form NH₄⁺ | Kidneys (proximal tubule, collecting duct), liver, general systemic tissues | Chemical equilibrium in cytosol & extracellular fluid | Critical for acid-base balance, especially in kidney (proximal tubule, collecting duct). NH₃ can diffuse across membranes; NH₄⁺ excreted in urine. | Not blocked by typical “drugs” | Disruption in ammonia handling → metabolic acidosis or alkalosis, depending on direction of imbalance |