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ATP

Adenosine (P1) receptors ATPase types ATP Receptors ATP-related Disorders Metabolism P2 Receptors External link: Klotho

ATP metabolism
Precursors:		ADP
Synthesizing enzymes:		Phosphorylases
Metabolizing enzymes:		Phosphatases ATPases
Metabolites:		ADP, AMP, Adenosine, Inosine

ATP Receptors (P2 purinoceptors) 1,2
Receptor subtypes	Agonists	Antagonists	Second messenger	Principal tissue
P2X1	α-β-Me-ATP ATP	α-β-Me-ATP (desensitizes) Suramin	Cation channel Ca++ & Na+   Influx into cell	Smooth muscle Sensory ganglia Cerebellum (Postsynaptic) Heart; Platelets
P2X2	ATP > ATP-γ-S	PPADS Suramin	Cation channel Ca++: Influx into cell	Autonomic ganglia Brain; Pituitary Sensory ganglia Smooth muscle Retina
P2X3	2-MeSATP > ATP	TNP-ATP PPADS α-β-Me-ATP (desensitizes) Suramin	Ion channel	Sensory ganglia Solitary tract neurons Sympathetic neurons
P2X4	ATP > α-β-Me-ATP	.	Cation channel Ca++: Influx into cell	Brain; Pancreas Testes; Colon Smooth muscle
P2X5	ATP > α-β-Me-ATP	PPADS Suramin	Ion channel	Heart; Gut; Bladder Autonomic ganglia Skin (Proliferating cells) Thymus; Spinal cord
P2X6	No function as   homomultimer	.	Ion channel	Skeletal muscle Brain Spinal motor neurons Autonomic ganglia
P2X7	dBz-ATP > ATP	KN62; KN04 Coomassie   brilliant blue	Cation channel Large pore with   prolonged activation	Apoptotic cells   Macrophages   Lymphocytes   Microglia   Skin
P2Y1	2-Me-S-ADP >   2-Me-S-ATP	MRS2279 MRS2179	Gq/Gn PLC-β activation	Muscle: NMJs Epithelium; Endothelium Immune cells; Platelets Osteoclasts
P2Y2	UTP = ADP	Suramin	Gq/Gn; ?Gi PLC-β activation	Epithelium; Endothelium Immune cells; Kidney Osteoclasts
P2Y4	UTP > ADP	RB2; PPADS	Gq/Gn; ?Gi PLC-β activation	Endothelial cells
P2Y6	UTP > ADP	RB2; PPADS Suramin	Gq/Gn PLC-β activation	Epithelial cells; Thymus T-cells; Placenta
P2Y11	ARC67085MX   > BzATP	RB2; Suramin	Gq/Gn & Gs PLC-β activation	Spleen; Intestine Granulocytes
P2Y12	ADP	ARC67085MX ARC69931MX	Gi Adenylyl cyclase   inhibiton	Platelets
P2T (platelet)	ADP 2-methylthioADP	ATP ARL67085	Negative: cAMP, ­ cation conductance
P2Z (mast cell)	ATP4-	none	?
P2U	UTP	none	PI; Ca++; G-protein

P2 receptors

• Types
  • P2X receptors are ATP-gated cation channel receptors, gating Na⁺, K⁺, and exceptionally Ca⁺⁺.
  • P2Y receptors are a family of G protein-coupled receptors.
  • P2Z receptors mediate non-selective pores in mast cells.
• Functional features
  • ATP and the P2X₁ receptor mediate transmission from nerve to smooth muscle as a co-transmitter system with noradrenaline.
  • ATP mediates rapid depolarization and phasic contraction.
  • Noradrenaline produces a slow maintained contraction due to the release of intracellular Ca⁺⁺ stores.
  • Neuropeptide Y
    • Also released at these synapses
    • Y₁ & Y₂ receptor mechanisms
      • Adenylyl cyclase inhibition
      • N- and P/Q channel inhibition
      • GIRK activation
      • MAPK activation
    • Presynaptic effects
      • Y₂ receptors
      • Inhibit presynaptic N & P/Q type Ca⁺⁺ channels involved in neurotransmitter release
    • Post-junctional effects
      • Y₁ receptors: Activate L-type Ca⁺⁺ channels
      • Y₂ receptors
        • Increase neuronal excitability
        • Mobilize intracellular Ca⁺⁺
        • Activate protein kinase C
      • Enhance actions of both ATP & noradrenaline
    • Anti-nociceptive effect
      • Inhibit excitatory interneurons & projection neurons in the dorsal horn (Y₁)
      • Inhibit glutamate release from dorsal root ganglion afferents (Y₁, Y₂)
    • Sympathetic vasomotor neuroeffector junction
      • Presynaptic inhibition of norepinephrine release (Y₂)
      • Potentiates vasoconstrictor effects of norepinephrine (Y₁)

P2X purinoreceptors

• Cation-selective ion channels
• Open on the binding of extracellular ATP
• Role: Fast synaptic transmission between neurones & from autonomic nerves to smooth muscles.
• Action
  • ATP is released as a neurotransmitter from central and peripheral nerves
  • ATP acts at P2X receptors to produce postsynaptic depolarization & excitation
• Subunit Structure
  • P2X receptors contain 397 to 595 amino acids
  • Regions
    • Intracellular N-terminus region: Short
    • Transmembrane domain
    • Large extracellular loop: Contains 10 conserved cysteines
    • Transmembrane domain
    • C-terminal intracellular tail
• Ionic pore
  • Formed by 3 or 4 subunits
  • Homomultimers: Formed by most P2X subunits; Not P2X₆
  • Heteromultimers
    • P2X_2/3; P2X_4/6; P2X_1/5; P2X_2/6
    • P2X₇ not part of multimers
  • P2X_2/3 inhibition: Dysgeusia
• P2RX₃ (P2X₃) receptors
  • Properties
    • Mediate currents in sensory neurons: Rapidly desensitizing
    • Not sensitive to pH
    • Antagonist: Crab spider Thomisus onustus venom peptide PT6 ⁸
  • Locations
    • Small dorsal root ganglion cells: Main P2X receptor
      • Capsaicin sensitive
      • Non-peptidergic
      • Label with lectin IB4
    • Trigeminal ganglion
      • Present on large & small sensory cell bodies & processes
      • Present on neurons projecting to skin & viscera
      • Not present on cells to skeletal muscle
    • Central projections: Inner lamina II of spinal dorsal horn
    • Solitary nucleus
    • Tubular viscera
  • Functions: Nociception
• P2RX4: Associated with allodynia
• P2RX7: Type 2 diabetes associations

	P2RX1	P2RX2	P2RX3	P2RX4	P2RX5	P2RX6
Brain	-	+	-	-	-	+
Spinal cord	+	+	-	+	+	+
Sensory ganglia	+	+	+	+	+	+
Superior cervical ganglion	+	+	-	+	-	+
Adrenal medulla	-	+	-	-	-	-
Smooth muscle	+	-	-	-	-	-

ATPase Types

• P-Family
  • Catalyze cation uptake and/or efflux driven by ATP hydrolysis
  • Cellular location: Plasma or endoplasmic reticular membranes
  • Examples
    • Na⁺, K⁺-ATPases (ATP1A; ATP1B): 3Na⁺ exchanged for 2K⁺ per ATP molecule hydrolyzed
    • Ca⁺⁺-ATPases (ATP2A; ATP2B; ATP2C): May catalyze Ca⁺⁺-K⁺ antiport
    • Gastric H⁺-translocating ATPases (ATP5): Replace H⁺ for Na⁺
  • Disorders
  • External link: TCDB
• F-ATPase Family
  • F-Type ATPases
    • Mitochondrial
    • Functional components
      • CF(1)
        • Catalytic core
        • 5 subunits: a, b, g, d, e
      • CF(0)
        • Membrane proton channel
        • 3 subunits: A, B, C
    • Pump 3-4 H⁺ out of mitochondria per ATP hydrolyzed
    • Example: Mitochondrial ATPase6
    • External link: TCDB
  • V-Type ATPases
    • Vacuolar
    • Acidifies intracellular compartments
    • Components
      • Peripheral catalytic V1 complex: Subunits A, B, C, D, E, AND F
      • Integral membrane V0 Protein Pore: Main component is proteolipid protein
    • Example: Brain isoform ATP6B2
    • Disorders
      • XMEA: VMA21
      • Osteopetrosis (OPTB1) : T cell immune regulator 1 (TCIRG1)
    • External link: TCDB
  • Disorders
• ABC-ATPase Family
  • ATP hydrolysis without protein phosphorylation energizes transport
  • Many subfamilies: Often grouped by transport substrate
  • Disorders
  • External link: TCDB
• AAA-ATPase family
  • ATP:ADP antiporters
  • Disorders
  • External link: TCDB

Adenine nucleotide translocators

• General characteristics
  • Most abundant mitochondrial proteins
  • Integral components of inner mitochondrial membrane
  • Facilitate exchange of ADP and ATP between cytosol & mitochondria
• Proteins
  • SLC25A4 (ANT 1) : Skeletal muscle
  • SLC25A5 (ANT 2)
  • SLC25A6 (ANT 3) : Liver
  • SLC25A16 : Graves Disease Carrier Protein (GDC)
  • SLC25A31 (ANT4)
• Disorders

ATP Disorders

• ATPase
  • Mitochondrial ATPase 6 syndromes (F-Type)
    • Leber's hereditary optic atrophy
    • Leigh's syndrome
    • NARP
    • Familial bilateral striatal necrosis
  • AAA ATPase (ATPases Associated with diverse cellular Activities) family syndromes
    • Familial spastic paraplegias
      • SPG7: Paraplegin; Mitochondrial
      • SPG4: Spastin; Nuclear ATPase
    • Optic atrophy syndromes
      • Developmental delay, Optic atrophy, Polyneuropathy: ATAD3A
      • Psychomotor delay, Optic atrophy, Ataxia: YME1L1
    • Encephalopathy, Cataracts, Neutropenia: CLPB
    • HIBM with Paget's & Dementia
      • Valosin-containing protein (VCP): Has 2 AAA domains
    • SCA 28: AFG3L2
    • AMC5 & Torsion dystonia (DYT1), Early-onset
      • torsin 1A
    • Refsum (Infantile) & Zellweger syndromes
      • Peroxisome biogenesis factor 1 (PEX1)
    • GRACILE syndrome: BCS1L
    • Fidgetin
      • Mouse disorder: Fidget
    • DCIDP: PSMC3
  • Congenital Cardiomegaly & Hepatomegaly: Mitochondrial ATPase deficiency
  • B₁₂ deficiency
    • K⁺/H⁺ ATPase: Antibody target
  • Brody syndrome: ATPase 2A1 (P-Family)
  • ATP1A1
    • CMT 2
  • ATP1A2
    • Migraine, Familial hemiplegic 2 , Dominant
    • Migraine, familial basilar
    • Alternating hemiplegia of childhood
    • Hypokalemic Periodic Paralysis + CNS
  • ATP1A3 ⁶
    • Common features
      • Paroxysmal events
      • Hyperkinesia
      • Neuropsychiatric symptoms,
      • Cognitive impairment
    • Dystonia 12
    • Childhood Dystonia-Ataxia-Parkinsonism, Rapid onset
    • Alternating hemiplegia of childhood 2
    • CAPOS
    • Polymicrogyria, de novo dominant ⁵
    • Epilepsy, Relapsing encephalopathy, Cerebellar ataxia (RECA)
    • Fever induced paroxysmal weakness & encephalopathy (FIPWE)
    • Developmental & epileptic encephalopathy 99 (DEE99)
    • Childhood onset schizophrenia (COS)
    • Spasticity & Intellectual disability, de novo
  • ATP1B2
  • ATP1G1 (FXYD2) : Na⁺-K⁺-ATPase, γ polypeptide
    • Renal magnesium loss, Dominant, Isolated
  • ATP2A2
    • Darier-White disease: Keratosis follicularis
    • Acrokeratosis verruciformis
    • Rhabdomyolysis, recurrent, Dominant
    • Vacuolar myopathy, Recessive
  • ATP2A3: Polymorphisms in elite wrestlers
  • ATP2B2
    • Deafness, Dominant (DFNA82)
    • Deafness, Recessive 12, modifier
    • Neurodevelopmental syndrome: Intellectual disability, Ataxia, Dystonia, Seizures; Dominant de novo ⁷
    • Deafwaddler (dfw) mouse: Deafness; Vestibular imbalance
  • ATP2B3
    • SCAX1
  • ATP2C1
    • Hailey-Hailey disease (Benign chronic pemphigus) : Blistering & erosions of skin
  • ATP5A1: Neonatal encephalopathy
  • ATP5F1D: Childhood encephalopathy
  • ATP6AP2: Parkinson-Spasticity
  • ATP6B1 : B-subunit of renal apical H⁺-ATPase pump
    • Distal renal tubular acidosis with deafness
  • ATP6N1B : Kidney-specific proton pump 116-kD accessory subunit
    • Distal renal tubular acidosis with preserved hearing (RTADR)
  • ATP6V0A1 : Neurodevelopmental disorder + Epilepsy & Brain atrophy (NEDEBA)
  • ATPase 7 (Cu⁺⁺ transporting; P-Type)
    • Wilson's : β polypeptide (ATP7B)
    • Menkes : α polypeptide (ATP7A)
    • Occipital horn syndrome : α polypeptide (ATP7A)
    • SMAX3 (ATP7A)
  • ATP8A2: Ataxia & Mental retardation (CAMRQ4)
  • ATP9A : Neurodevelopmental disorder with poor growth & behavioral abnormalities (NEDGBA)
  • ATP10C (P-Family; Ca⁺⁺ transporting)
    • Maternally expressed
    • Expression absent in Angelman syndrome
    • Deletions in mice associated with increased body fat
  • ATP11A
    • Leukodystrophy, Hypomyelinating 24 (HLD24)
    • Deafness, Autosomal-dominant 84 (DFNA84)
  • ATP12: Mitochondrial disorder
  • T cell immune regulator 1 (V-type ATPase)
    • Infantile malignant osteopetrosis
  • Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1)
    • Ossification of posterior longitudinal ligament: Susceptability
• Adenine nucleotide translocators
  • ANT 1 (SLC25A4)
    • Diseases
      • PEO 2/PEO 3
      • Hypertrophic cardiomyopathy
    • Mouse knockout
      • Deficiency in muscle
      • Clinical: Rapid fatigue; Dyspnea
      • Mitochondrial dysfunction
  • SLC25A16 (Graves Disease Carrier Protein (GDC))
    • ADP/ATP carrier protein
    • Target of IgG autoantibodies in Graves disease
• ATP-binding cassette (ABC) transporters
  • ATP-binding cassette A1 (ABCA1) : Tangier disease
  • ATP-binding cassette A2 (ABCA2)
    • Intellectual Developmental disorder with Poor Growth ± Seizures or Ataxia (IDPOGSA)
    • Polymorphisms: Associated with early onset Alzheimer disease
  • ATP-binding cassette A3 (ABCA3) : Surfactant deficiency, neonatal (Respiratory distress syndrome)
  • ABCA4
    • Macular degenerations (Stagardt & Age-related 2 )
    • Retinitis pigmentosa 19
    • Cone-rod dystrophy 3
    • Structure: HPRD
  • ATP-binding cassette A7 (ABCA7) : Sjogren syndrome autoantigen SS-N
  • ABCA12 : Lamellar ichthyosis 2 ; Harlequin Ichthyosis
  • ABCB1
    • Colchicine resistance
    • Docetaxel neuropathy
    • Inflammatory bowel disease 13
    • Encephalopathy, acute transient (ENPAT)
  • ABCB2 (TAP1) :
    • Mouse knockout reduces
    • CNS: Activity-dependent remodeling; Plasticity of connections
    • MHC I expression in cells
  • ABCB3 (TAP2) : Bare Lymphocyte Syndrome Type I ; Wegener-like granulomatosis
  • ABCB4 : Cholestasis, Progressive familial intrahepatic 3
  • ABCB5 : Expressed in melanomas; Correlate with doxorubicin resistance
  • ABCB6
    • Locations: Mitochondria, Outer membrane; Secretory pathway
    • Role: Porphyrin transport
    • Disease: Ocular coloboma
  • ABCB7 : Sideroblastic anemia & Spinocerebellar ataxia (XLSA/A)
  • ABCB8 : Mitochondrial
  • ABCB9 : Lysosomal
  • ABCB10 : Mitochondrial
  • ABCB11 : Cholestasis, Progressive familial intrahepatic 2
  • ABCC2 : Dubin-Johnson syndrome: Multidrug resistance-associated protein
  • ABCC6
    • Anthracycline resistance-associated protein
    • Transports glutathione conjugates
    • Diseases
      • Pseudoxanthoma elasticum
      • Arterial calcification, generalized, of infancy, 2
  • ABCC7 (CFTR) : Cystic fibrosis ; Congenital bilateral aplasia of vas deferens; ; Sarcoid susceptibility
  • ABCC8 (Sulfonylurea receptor 1; SUR1)
    • Regulatory subunit of ATP-sensitive potassium (K_ATP) channel (Kir 6.1 or 6.2)
    • Disorders
      • Persistent hyperinsulinemic hypoglycemia of infancy (HFF1) : Loss of function mutations
      • Neonatal diabetes mellitus, permanent (PNDM3) : Activating mutations
      • Diabetes mellitus, noninsulin-dependent
      • Diabetes mellitus, transient neonatal 2 (TNDM2)
      • Hypoglycemia of infancy, leucine-sensitive (LIH)
  • ABCC9 (Sulfonylurea receptor 2; SUR2)
    • Function: Regulatory subunit of ATP-sensitive potassium (K_ATP) channel (Kir 6.1 or 6.2)
    • Disorders
  • ABCC11 : Wet/Dry ear wax (Gly180Arg)
  • ABCD1 (ALD) : Adrenomyeloneuropathy (Adrenoleukodystrophy protein (ALDP))
  • ABCD2 (ALDR) : Cerebellar Purkinje & DRG ganglion cell loss in mouse knockout
  • ABCD3
    • Zellweger syndrome 2 (Peroxisomal membrane protein)
    • OPDM
  • ABCD4
    • Encephalopathy + Bone marrow failure
    • Disease mechanism: Failure to release vitamin B₁₂ from lysosomes
  • ABCG5 : Sitosterolemia
  • ABCG8 : Sitosterolemia
• Cyclic nucleotide gated (CNG) channels
  • Retinitis pigmentosa
  • Rod monochromacy (Total colorblindness)
• P2X7 channel : Chronic lymphatic leukemia, susceptibility

Adenosine (P1) Receptors 2
Receptor subtypes	Agonists	Antagonists	Second messenger	Principal tissue
A1	CCPA; CPA	DPCPX; CPX; XAC	Gi (1-3): Reduced cAMP	Brain; Spinal cord Testes; Heart Autonomic nerve terminals
A2A	CGS21680	KF17837; SCH58261	Gs: Increased cAMP	Brain; Heart Lungs; Spleen
A2B	NECA	Enprofylline	Gs: Increased cAMP	Large intestine Bladder
A3	IB-MECA DBX RM	MRS1220; L268605	Gi, Go/n:   Reduced cAMP   Increased Ins(1,4,5)P3	Lung, Liver Brain, Testes Heart