Molecule Information

General Information of the Molecule (ID: Mol04321)

• Name: Protein kinase C gamma type (PRKCG) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: PRKCG
• Gene ID: 5582
• Sequence:
  MAGLGPGVGDSEGGPRPLFCRKGALRQKVVHEVKSHKFTARFFKQPTFCSHCTDFIWGIG
  KQGLQCQVCSFVVHRRCHEFVTFECPGAGKGPQTDDPRNKHKFRLHSYSSPTFCDHCGS
  L LYGLVHQGMKCSCCEMNVHRRCVRSVPSLCGVDHTERRGRLQLEIRAPTADEIHVTVG
  EA RNLIPMDPNGLSDPYVKLKLIPDPRNLTKQKTRTVKATLNPVWNETFVFNLKPGDVE
  RRL SVEVWDWDRTSRNDFMGAMSFGVSELLKAPVDGWYKLLNQEEGEYYNVPVADADNC
  SLLQ KFEACNYPLELYERVRMGPSSSPIPSPSPSPTDPKRCFFGASPGRLHISDFSFLM
  VLGKG SFGKVMLAERRGSDELYAIKILKKDVIVQDDDVDCTLVEKRVLALGGRGPGGRP
  HFLTQL HSTFQTPDRLYFVMEYVTGGDLMYHIQQLGKFKEPHAAFYAAEIAIGLFFLHN
  QGIIYRD LKLDNVMLDAEGHIKITDFGMCKENVFPGTTTRTFCGTPDYIAPEIIAYQPY
  GKSVDWWS FGVLLYEMLAGQPPFDGEDEEELFQAIMEQTVTYPKSLSREAVAICKGFLT
  KHPGKRLGS GPDGEPTIRAHGFFRWIDWERLERLEIPPPFRPRPCGRSGENFDKFFTRA
  APALTPPDRL VLASIDQADFQGFTYVNPDFVHPDARSPTSPVPVPVM
• Function: Calcium-activated, phospholipid- and diacylglycerol -dependent serine/threonine-protein kinase that plays diverse roles inneuronal cells and eye tissues, such as regulation of the neuronalreceptors GRIA4/GLUR4 and GRIN1/NMDAR1, modulation of receptors andneuronal functions related to sensitivity to opiates, pain and alcohol,mediation of synaptic function and cell survival after ischemia, andinhibition of gap junction activity after oxidative stress. Binds andphosphorylates GRIA4/GLUR4 glutamate receptor and regulates itsfunction by increasing plasma membrane-associated GRIA4 expression. Inprimary cerebellar neurons treated with the agonist 3,5-dihyidroxyphenylglycine, functions downstream of the metabotropicglutamate receptor GRM5/MGLUR5 and phosphorylates GRIN1/NMDAR1 receptorwhich plays a key role in synaptic plasticity, synaptogenesis,excitotoxicity, memory acquisition and learning. May be involved in theregulation of hippocampal long-term potentiation , but may be notnecessary for the process of synaptic plasticity. May be involved indesensitization of mu-type opioid receptor-mediated G-proteinactivation in the spinal cord, and may be critical for the developmentand/or maintenance of morphine-induced reinforcing effects in thelimbic forebrain. May modulate the functionality of mu-type-opioidreceptors by participating in a signaling pathway which leads to thephosphorylation and degradation of opioid receptors. May alsocontributes to chronic morphine-induced changes in nociceptiveprocessing. Plays a role in neuropathic pain mechanisms and contributesto the maintenance of the allodynia pain produced by peripheralinflammation. Plays an important role in initial sensitivity andtolerance to ethanol, by mediating the behavioral effects of ethanol aswell as the effects of this drug on the GABA receptors. During andafter cerebral ischemia modulate neurotransmission and cell survival insynaptic membranes, and is involved in insulin-induced inhibition ofnecrosis, an important mechanism for minimizing ischemic injury.Required for the elimination of multiple climbing fibers duringinnervation of Purkinje cells in developing cerebellum. Is activated inlens epithelial cells upon hydrogen peroxide treatment, andphosphorylates connexin-43 , resulting in disassembly ofGJA1 gap junction plaques and inhibition of gap junction activity whichcould provide a protective effect against oxidative stress . Phosphorylates p53/TP53 and promotes p53/TP53-dependentapoptosis in response to DNA damage. Involved in the phase resetting ofthe cerebral cortex circadian clock during temporally restrictedfeeding. Stabilizes the core clock component BMAL1 by interfering withits ubiquitination, thus suppressing its degradation, resulting inphase resetting of the cerebral cortex clock .Phosphorylates and activates LRRK1, which phosphorylates RAB proteinsinvolved in intracellular trafficking .{ECO:0000250|UniProtKB:P63318, ECO:0000250|UniProtKB:P63319,ECO:0000269|PubMed:16377624, ECO:0000269|PubMed:36040231}.
• Uniprot ID: KPCG_HUMAN
• Ensembl ID: ENSG0000012658312
• HGNC ID: HGNC:9402

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Sitagliptin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Epilepsy [ICD-11: 8A60.0] [1]

• Sensitive Disease: Epilepsy [ICD-11: 8A60.0]
• Sensitive Drug: Sitagliptin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: Wistar rats model; Rattus norvegicus
• Experiment for Molecule Alteration: Protein kinase assay; RT-qPCR
• Experiment for Drug Resistance: Experimental Animal Model
• Mechanism Description: Mechanistic insights revealed sitagliptin's ability to modulate the seizure grade and first myoclonic jerk latency via oxidative stress markers, like reduced glutathione and glutathione peroxidase emphasizing its antioxidative role in epilepsy. Additionally, it demonstrated anti-inflammatory effects by significantly reducing proinflammatory markers interleukin-1beta and interleukin-6. The modulation of key genes of the long-term potentiation pathway, particularly protein kinase C-gamma and metabotropic glutamate receptor 5, was evident through mRNA expression levels. Finally, sitagliptin showed potential neuroprotective properties, limiting pentylenetetrazolium-induced neuronal loss in the hippocampal region. Collectively, our findings suggest sitagliptin's multidimensional therapeutic potential for drug-resistant epilepsy specifically via a long-term potentiation pathway by inhibiting protein kinase C-gamma.

References

• Ref 1: Unlocking the Therapeutic Potential: Sitagliptin's Multifaceted Approach in Drug-Resistant Epilepsy through a Novel Mechanism Inhibiting Protein Kinase C-gamma and a Long-Term Potentiation Pathway. ACS Pharmacol Transl Sci. 2024 May 14;7(6):1856-1863.